Next Article in Journal
Proof of Concept of the Contribution of the Interaction between Trait-like and State-like Effects in Identifying Individual-Specific Mechanisms of Action in Biological Psychiatry
Next Article in Special Issue
Gender and Psychosocial Differences in Psychological Resilience among a Community of Older Adults during the COVID-19 Pandemic
Previous Article in Journal
Robotic Mediastinal Tumor Resections: Position and Port Placement
Previous Article in Special Issue
Gender Differences in Acute Aortic Dissection
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JPM
Volume 12
Issue 8
10.3390/jpm12081196
jpm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Sex-Related Differences of Matrix Metalloproteinases (MMPs): New Perspectives for These Biomarkers in Cardiovascular and Neurological Diseases

by
Alessandro Trentini
1,2,†,
Maria Cristina Manfrinato
2,3,†,
Massimiliano Castellazzi
2,3,4,* and
Tiziana Bellini
2,3
1
Department of Environmental and Prevention Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy
2
University Center for Studies on Gender Medicine, University of Ferrara, 44121 Ferrara, Italy
3
Department of Neuroscience and Rehabilitation, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy
4
Interdepartmental Research Center for the Study of Multiple Sclerosis and Inflammatory and Degenerative Diseases of the Nervous System, University of Ferrara, 44121 Ferrara, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to the work.
J. Pers. Med. 2022, 12(8), 1196; https://doi.org/10.3390/jpm12081196
Submission received: 22 June 2022 / Revised: 19 July 2022 / Accepted: 20 July 2022 / Published: 22 July 2022
(This article belongs to the Special Issue Personalized Medicine Interdisciplinary Aspects and Sex Gender-Specific Differences)
Browse Figures
Review Reports Versions Notes

Abstract

:
It is now established that sex differences occur in clinical manifestation, disease progression, and prognosis for both cardiovascular (CVDs) and central nervous system (CNS) disorders. As such, a great deal of effort is now being put into understanding these differences and turning them into “advantages”: (a) for the discovery of new sex-specific biomarkers and (b) through a review of old biomarkers from the perspective of the “newly” discovered sex/gender medicine. This is also true for matrix metalloproteinases (MMPs), enzymes involved in extracellular matrix (ECM) remodelling, which play a role in both CVDs and CNS disorders. However, most of the studies conducted up to now relegated sex to a mere confounding variable used for statistical model correction rather than a determining factor that can influence MMP levels and, in turn, disease prognosis. Consistently, this approach causes a loss of information that might help clinicians in identifying novel patterns and improve the applicability of MMPs in clinical practice by providing sex-specific threshold values. In this scenario, the current review aims to gather the available knowledge on sex-related differences in MMPs levels in CVDs and CNS conditions, hoping to shed light on their use as sex-specific biomarkers of disease prognosis or progression.

1. Introduction

Biologically based differences between the sexes impact several aspects of human life, starting from development to the construction of behaviour [1]. However, sex differences are also able to influence both health and disease, impacting biomedical research as well as individual and public health and healthcare delivery [2,3].
A remarkable aspect is that sex differences may influence susceptibility to a disease or its progression at both molecular and epidemiological levels [4]. This is evident by looking at the point global estimates for disability-adjusted life-year (DALY) disaggregated by sex, which represents both a measure of disease burden and a proxy for disease prevalence (Figure 1).
As displayed, virtually all conditions show a sex-driven disparity or a gender bias for injuries, but two conditions are of paramount importance when dealing with sex differences: cardiovascular diseases (CVDs) and neurological disorders. This is particularly true considering that CVDs are a leading cause of death, whereas neurological disorders strongly impact the quality of life of affected patients [5,6]. For these reasons, such conditions are constantly studied from a prevention and treatment point of view, and accumulating evidence suggests that both share an underlying sex difference [4]. As displayed in Figure 1, CVDs are characterized by a male-driven DALY, whereas neurological conditions (including stroke) present almost an equal proportion of both sexes. Although the exact causes for such differences are still largely unknown, the general knowledge about the matter in both disease groups is increasing. Despite this, a great deal of information is still lacking about the mechanisms of sex bias in most of the studies on biomarkers [7].
This is true also for matrix metalloproteinases (MMPs), enzymes responsible for extracellular matrix (ECM) turnover in both physiological states and diseases, that have been largely linked to both disorders [8,9]. For instance, high blood and cerebrospinal fluid levels of MMPs have been associated with an impaired blood–brain barrier (BBB) permeability, a fact that is directly correlated with increased infiltration of immune cells within the central nervous system (CNS) [10,11]. The same is true for CVDs, where high concentrations of MMPs have been related to atherosclerotic plaque instability and worse outcome [12]. Thus, considering the involvement of these important enzymes in such disorders, it is compelling to observe whether sex can impact MMPs expression in these diseases. To the best of our knowledge, no meta-analysis or updated review exists on this matter.
Therefore, in the attempt to fill in the gap, we aimed at gathering the available knowledge on potential sex-related differences in MMPs levels in CVDs and CNS conditions, hoping to shed light on their possible use as sex-specific biomarkers of disease prognosis or progression. To this end, after a brief introduction to the biochemistry of MMPs and their involvement in CVDs and CNS conditions, we will shift the focus to all the present information about sex differences.

2. Search Strategy and Data

We conducted a literature search in MEDLINE for all studies in the English language without age restriction, published any time to May 2022 with the keywords “MMPs” AND “neurodegenerative disorders” OR “neurodegenerative diseases” AND “sex difference” OR “gender difference”, in the title or abstract. The same criteria were followed for CVDs, with the keywords “MMPs” AND “cardiovascular disorders” OR “cardiovascular diseases” AND “sex difference” OR “gender difference”. To avoid missing possible articles on the matter, we repeated the literature search also separating by pathology. For neurodegenerative disorders, the keywords “Parkinson’s disease”, “Multiple Sclerosis”, “Alzheimer’s disease”, “Epilepsy”, “Ischemic stroke”, “Haemorrhagic stroke”, “Stroke”, “Migraine” were alternatively associated with AND “MMPs” AND/OR “sex difference”/“gender difference”. For CVDs, the keywords “Rheumatic Heart Disease”, “Hypertensive disease”, “Ischemic Heart disease”, “Coronary heart disease” OR “CAD”, “Cardiomyopathy”, “Myocarditis”, “Endocarditis”, “Myocardial infarction”, “Aneurism”, were alternatively associated with AND “MMPs” AND/OR “sex difference”/“gender difference”. We also searched for possible interesting articles on the matter by looking into reviews.
The data of global estimates of disability-adjusted life-year (DALY) disaggregated by sex and pathology were derived from the study Global Burden of Disease Study 2019 (GBD 2019) (https://vizhub.healthdata.org/gbd-results/, accessed on 12 July 2022).

3. Matrix Metalloproteinases

As already said, MMPs are important zinc-dependent endoproteases involved in both physiological and pathological ECM remodelling [13]. For instance, they are involved in reproductive growth, embryonic development and morphogenesis during pregnancy, bone remodelling, tissue repair, and wound healing [14]. Being produced as zymogens, their net activity on tissues is a careful balance between activation processes and inhibition by specific inhibitors (tissue inhibitors of matrix metalloproteinases, TIMPs) and not specific ones (e.g., α2-macroglobulin) [15]. Thus, alterations in MMPs expression, activity/activation, and inhibition cause an accelerated ECM breakdown leading to a pathological condition, as happens in CVDs, musculoskeletal disorders, and various cancers [16,17,18,19].
MMPs have also been implicated in other processes such as systemic inflammation and CNS disorders, playing a pivotal role in the proteolytic degradation of the blood-brain barrier [10,11,20]. Collectively, circulating levels of MMPs have been proposed as potential markers of many cardiovascular and neurological diseases [8,9]. Before examining the potential influence of sex on the circulating levels of MMPs, we will briefly focus on the general structure of MMPs.

3.1. Structure and Function of MMPs

3.1.1. General Structure and Regulation

This family of calcium- and zinc-dependent endopeptidases comprises more than 25 members divided into six classes based on their ability to degrade various components of the ECM: collagenases (MMP-1, MMP-8, MMP-13, MMP-18), gelatinases (MMP-2, MMP-9), stromelysins (MMP-3, MMP-10, MMP-11), matrilysins (MMP-7, MMP-26), membrane-type MMPs anchored to the cell membrane by a transmembrane (TM) domain or by a glycosylphosphatidylinositol (GPI)-anchored domain, and “other MMPs” [21,22,23]. Collagenases and gelatinases alter the molecules of the basal lamina, subsequently leading to cell death. In particular, collagenases degrade triple-helical fibrillar collagen in bone and ligaments, whereas gelatinases are involved in different cellular processes including angiogenesis and neurogenesis [14]. Stromelysins are small proteases that degrade segments of the ECM, and matrilysins process cell surface molecules and digest ECM components [14]. Finally, MT-MMPs have collagenolytic activity and may activate some proteases and components of the cell surface [24,25].
From a structural point of view (Figure 2), the MMP family shares a high homology, with a conserved zinc-binding motif (HEXXHXXGXXH) in the catalytic domain [26,27] and a common core structure consisting of a pro-peptide of about 80 amino acids, a catalytic domain of about 170 amino acids, a linker peptide called hinge region of variable length, and a hemopexin domain of about 200 amino acids. In addition, MMPs contain an amino-terminal signal sequence removed in the secretory pathway, targeting the enzyme to the endoplasmic reticulum (Figure 2, in grey) [28].
Four important divalent cations are embedded within the catalytic domain, possessing different roles: one zinc ion is coordinated by three histidines in the catalytic cleft and is essential in the polarization of water molecules necessary for the hydrolysis of the peptidic bond [28]. Within the same domain, another zinc ion and at least two calcium ions are essential to maintain the correct spatial structure for the interaction of substrates with the active site [28].
The hinge region (Figure 2, in dark blue) serves as a linking sequence to allow the free movement between the catalytic and hemopexin domains [28]. A carboxy-terminal (C-terminal) hemopexin-like (PEX) domain, with a four-bladed β-propeller structure connected to the hinge region, is usually involved in substrate recognition and inhibitor binding [29]. Additionally, different classes of MMPs have peculiar structural features that distinguish them from the prototypical MMP structure: for instance, gelatinases (MMP -2 and MMP-9) have a fibronectin-like domain inserted within the catalytic domain that facilitates both gelatin and collagen binding [30].
MMPs are maintained into an inactive form by a pro-peptide domain, which should be removed to convert the enzyme into the active form, an event that usually happens in the extracellular space through other proteolytic enzymes such as serine proteases, plasmin, or other MMPs [14]. As an exception, some MMPs have a furin recognition site before the catalytic domain, allowing the intracellular activation of the enzyme by furin [10,21].
Other pathophysiological activation pathways include the modification of the thiol group of the cysteine in the pro-domain and are responsible for maintaining the enzyme inactive by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Such modification leads to the oxidation of the side chain of the amino acid with S-nitrosylation or S-glutathionylation being the predominant changes [31,32].
The expression and activity of MMPs are regulated at many levels. At the transcriptional level, the synthesis of new MMPs is regulated by various cytokines, growth factors, and ROS [33].
Once synthesized, the activity of MMPs depends on the activation of their latent form as well as on endogenous tissue inhibitors, namely α2-macroglobulins and TIMPs [22], which bind to the enzymes suppressing the activity. When the activity is not well-balanced by a fine-tuned inhibition, a transition from physiological to pathological condition occurs [14].
Currently, four TIMPs have been described (from TIMP-1 to TIMP-4), with TIMP-1 and TIMP-2 being the most studied. Interestingly, TIMP-2 can participate in both inhibition and activation of enzymes by forming 1:1 stoichiometric non-covalent complexes [34].
A particular mention must be made for MMP-9, which belongs to the gelatinase subfamily. While the inactive form of MMP-9 (proMMP-9) is usually secreted in a complex with TIMP-1 [35], it also exists in a TIMP-1 free form released by neutrophils [36]. In addition, there are at least two active forms of MMP-9 in body fluids: an N-truncated active enzyme that can be regulated by TIMP-1 and a “fully activated” enzyme lacking both the N- and C-terminal hemopexin domains, which cannot be inhibited by TIMP-1 at physiological concentrations [37,38].

3.1.2. Role of MMPs in CVDs

As said before, MMPs can be largely modulated by cytokines and growth factors, molecules that are produced during inflammatory conditions. As expected, inflammation is a cornerstone in most of the CVDs [39] and acts by deranging the delicate axis between MMP activation and inhibition. For instance, MMP activation can alter the architecture of atherosclerotic plaque helping its disruption [40]. However, their role is not just relegated to the “simple” plaque instability, but they also participate in a plethora of cardiovascular conditions including aneurism, myocardial infarction, atherosclerosis, hypertension, and cardiomyopathies (Table 1).
In aneurism, MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 are overexpressed within the aortic wall, participating in the weakening of ECM structure through the degradation of several collagens, elastin, and fibronectin [49,50].
A role in myocardial infarction (MI) has been found as well although is still far to be clear and somewhat complicated. MMPs seem to be involved in both healing processes after MI injury [57,58] as well as in the adverse remodelling that occurs after MI [52,59,60,61]. Interestingly, if the cytokine production following MI is controlled, an appropriate wound healing response is established, where MMPs, especially MMP-9 and MMP-2, actively participate in the process by degrading the ECM, favouring the infiltration of inflammatory cells and processing cytokines and chemokines [51]. However, if the production of MMPs is actively sustained well beyond the first 72 h (the period after the initial wound healing is complete), their action could be harmful [62].
One pathogenic mechanism by which MMPs can contribute to atherosclerosis is through the enhancement of vascular smooth muscle cell migration and the formation of neointima after a vascular injury [63,64]. In addition, as said before, active MMPs produced within the atherosclerotic lesion may contribute to plaque instability: in particular, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-12 have been connected to plaque development and a worse outcome [52,53,54,55,56].
A connection has also been found between MMPs and hypertension [41]. In particular, MMP-2 was increased in the thoracic aortas and heart of a model of hypertensive rat, where it may participate in hypertension-induced vascular remodelling [42,65,66]. This may be partially mediated by the ability of some MMPs to cleave receptors and factors responsible to maintain the vascular tone. For instance, MMP-7 and MMP-9 injection in spontaneously hypertensive rats (SHR) causes vasoconstriction, thereby increasing the blood pressure [43]. This may be due to a not yet well-characterized increase in MMP-dependent β2-adrenergic shedding. In addition, in vitro studies have found that MMP-2 can cleave factors that can increase vasoconstriction activity [67] or limit their vasodilating effect [44,45].
Finally, a growing body of evidence points toward MMP-2 as a major player in cardiomyopathies. For instance, the overexpression of active MMP-2 alone in the heart of transgenic mice models of ischemia/reperfusion can increase the infarct area and decrease the contractile function of the hearth [46]. On the contrary, the deletion of MMP-2 seems to be protective toward the heart remodelling and functionality following injury [68]. This might be at least partially related to the ability of MMP-2 to process several cardiac proteins including troponin I and myosin light chain [47,48].

3.1.3. Role of MMPs in Neurological Conditions

Within the CNS, MMPs participate both in (i) physiological processes such as neurogenesis, axonal guidance, synaptic plasticity, learning, and memory [69] and (ii) in pathological conditions such as neuroinflammation, neurodegeneration, and cerebrovascular related disorders [70].
Matrix metalloproteinases can be produced by several CNS-related cells, including endothelial cells, microglia, oligodendrocytes, neurons, and astrocytes [71]. Under normal conditions, MMPs have been observed to be (i) generally absent or (ii) at undetectable or (iii) otherwise modest levels in the mature brain [20]. A dysregulation of MMP activity and/or the presence of upregulatory stimuli could alter the physiological balance, inducing a pro-inflammatory state [72,73].
The MMPs most involved in brain processes are MMP-2, MMP-3, MMP-9, MMP-10, and MMP-14 [74,75] (Table 2).
While MMPs are considered generally absent, or in any case scarcely detectable in the CNS, MMP-2 seems to be an exception because it is physiologically expressed also in the healthy brain and cerebrospinal fluid (CSF) [74].
In pathological conditions, MMPs may increase blood–brain-barrier (BBB) permeability by acting on the basal lamina and tight junctions in endothelial cells, resulting in the final common pathway of acute neuroinflammatory damage [74,87].
In Alzheimer’s disease (AD), MMP-2 might be assumed to have a protective role [76], and in MS, active MMP-2 was associated with the remission phase of the disease, suggesting a role of this enzyme in the termination of MS neuroinflammation [77].
If, on the one hand, MMP-3 was physiologically associated with synaptic plasticity, learning, and neuronal development, in the other, uncontrolled MMP-3 activity was associated with Alzheimer’s and Parkinson’s diseases (AD and PD) [78,88].
MMP-9 is probably the most studied MMP in CNS disorders, especially in association with neuroinflammation. MMP-9 was associated with demyelination in MS [80], neuronal cell death in AD [81], neuroinflammation in PD [20], dolichoectasia [82,83], and neuroinflammation and cell death in amyotrophic lateral sclerosis (ALS) [84,85]. In hypoxic-ischemic lesions, MMP-2, MMP-3, and MMP-9 together increase the permeability of the BBB with a consequent greater risk of haemorrhagic transformation [74].
Finally, MMP-10 inhibition cleaves huntingtin and reduces cell death [86].

4. Sex Differences in MMPs and Pathologies

4.1. Sex Differences in MMPs and Cardiovascular Diseases

Cardiovascular diseases have long been seen as conditions that primarily affect males [4]. This conclusion can be drawn also by looking at Figure 1, where males account for almost 58% of the CDV group of DALY. However, the age-corrected risk of CVDs is similar between males and females [89] since it becomes equal between sexes after menopause or even increases for females. Nonetheless, by separating CVDs into several categories, we can see that the situation is more complex. Indeed, ischemic heart disease; the spectrum of disorders including cardiomyopathy, myocarditis, and endocarditis; and aneurism are far more frequent in males than females (Figure 3). On the other hand, females seem primarily affected by rheumatic and hypertensive heart disease (Figure 3).
Despite this evidence and the impact that sex hormones have on the expression of MMPs [79], the reports about a cross-interaction between MMPs, CVDs, and sex are still in their infancy. According to what is present in the literature, the most studied MMPs showing a sex difference in CVDs are MMP-2, MMP-3, MMP-9, MMP-8, MMP-13, and MMP-14 although the information on the last two members is scarce (see below for detailed information).
The results about sex disparity of MMP-2 in CVDs are conflicting and at variance with the considered condition. For instance, male patients affected by aneurysms have shown increased levels of MMP-2 in the aorta [90], a fact confirmed also in vivo in the mouse model [91] and in vitro on rat smooth muscle cells [92]. However, the opposite was found in females when considering patients with bicuspid valve thoracic aortic aneurysm (BV-AAA) [93,94]. This apparent contradiction could be explained by the fact that females affected by BV-AAA also show an extensive remodelling of the aorta [95], which is characterized by a decrease in deposition of ECM components and by increased degradation operated essentially by MMPs [96]. Finally, the levels of the MMP-2 were found elevated in the hearts of male rats during acute myocardial infarction (MI) [97], with higher serum levels of the enzyme found to be associated with lower myocardial fibrosis only in females [98].
MMP-3 is one of the enzymes that demonstrated an undeniable increase in males with respect to females in most of the studies dealing with MI [99,100,101]. In addition, serum MMP-3 was positively correlated with inflammatory markers only in females [101]. Collectively, these results may suggest, at least partly, a different interaction between sex and inflammation in the etiopathogenesis of MI [101].
The reports on MMP-8 (a.k.a. called neutrophil collagenase), which has specificity towards type I, II, and III collagens, are few, and all found decreased levels of the enzyme or no change in females suffering from thoracic aortic aneurysm [94] or in atherosclerotic plaques [102,103], suggesting a protective effect of sex hormones in females, at least in aneurysm [104].
MMP-9 is far, together with MMP-2, the most studied metalloprotease in all aspects of CVDs, especially considering its connection with inflammation [105]. Most of the studies present in the literature have found an increase in the ascending aorta of male patients affected by aneurysms [90,93,106], with only one report finding the opposite result in females [91]. The former results are in large agreement with the clinical observation of a higher prevalence of aneurysms in males, making it a striking example of male disadvantage in CVDs [104].
In MI, MMP-9 has been found to increase in the heart of male rats and mice when compared to females [97,107] and is associated with increased rupture of the left ventricle [108]. Although the fibrotic event seems not associated with different levels of the enzyme between the sexes, only in females are high MMP-9 serum concentrations correlated with markers of myocardial fibrosis [98].
Human coronary disease patients show contrasting results, with reports suggesting an increase in serum of males [109,110], whereas others found the opposite in females [111,112]. Collectively, it is undoubted that MMP-9 plays a key role in the aetiology of several CVDs, and it may point toward a different use of this protein as a sex-specific biomarker.
The preliminary results about MMP-13 and MMP-14 found in humans and confirmed in rats suggest an increased activity and production of both proteins in males affected by aneurism [94,113]. This is consistent with an increased ECM degradation and weakened aortic wall that makes males more prone to rupture. Again, this confirms the male disadvantage, present in certain cardiac conditions, over females.
The studies on sex-driven MMP expression in myocarditis are preliminary, and the only work we found in mice observed an increase in MMP-8 expression in the heart during myocarditis [114]. This may have an implication for myocardial remodelling and fibrosis during this condition [114]. Regarding rheumatic heart disease, despite several works found an increased expression of MMP-1 and MMP-9 in the mitral valve [115] and/or serum [116,117,118] of patients compared to controls, correlated with the underlying inflammation, there is currently no single study that explored a possible influence of sex on MMP expression. Sex-related differences in MMPs in patients affected by CVDs are summarized in Table 3.

4.2. Sex Differences in MMPs and CNS Disorders

Sex differences in the CNS are quite evident and touch several aspects of the brain. For instance, sex hormones affect brain anatomy in a region-specific manner, by influencing neuronal growth and development [123]. The brain is also affected at the biochemical/neurochemical level. As an example, females synthesize far less serotonin than their male counterparts, making them more susceptible to depression [124]. In addition, metabolic differences between males and females have been found in several regions of the brain [125]. Finally, various psychological and cognitive processes can be influenced as well [126].
The fundamental sex differences found in the anatomy, biochemistry, and genetics of a healthy brain translate also into a sex-driven disparity in susceptibility, progression, symptom severity, and pathology of disorders affecting the CNS [127]. This is clear also by looking at Figure 4. Indeed, most neurological conditions are characterized by a female-shifted disease burden, underlying an increased prevalence of neurological diseases in this sex. The only exceptions appear to be PD, epilepsy, haemorrhagic stroke, and ALS, where a male prevalence is documented [128,129,130,131]. Of note, the apparent counterintuitive lack of difference in neurological conditions shown in Figure 1 is mainly due to the inclusion of stroke-related diseases in this group. In fact, by leaving stroke within the CVDs, the sex bias in neurological conditions appears to be more evident (DALYs*100,000 population (95% Uncertainty Level), males: 413 (251–646); females: 565 (303–953)). For this reason, it is of paramount importance that the effect of sex is evaluated also in each condition separately to avoid possible misinterpretations driven by grouping variables.
From the data reported in the literature, it seems clear that one of the major implications of MMPs in CNS disorders occurs at the level of regulation of the BBB [10]. It is interesting to highlight how previous studies have demonstrated the ability of the hormone 17β-oestradiol to reduce the degradation of tight junction proteins by suppressing the upregulation of MMP expression [74], thus making oestrogens play a protective role towards the degradation of BBB [132]. From a clinical point of view, a growing number of articles are highlighting the existence of a sexual dimorphism in the CSF protein content resulting in higher levels in men than in women regardless of age [133,134]. The cause of this dimorphism seems to be attributable to a greater permeability to plasma proteins, especially albumin and IgG, of the blood–CSF barrier (BCSFB), as has been shown in patients with MS and patients with other inflammatory and non-inflammatory neurological disorders [135], in psychiatric patients [136], in subjects to whom lumbar puncture was performed for diagnostic purposes, and in healthy subjects [137].
A difference between sexes in BBB permeability was also confirmed using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) [138]. In that study, the authors demonstrated a better BBB integrity in cingulate and occipital cortices in females than in male non-demented elderly subjects. They also found that this sex-related difference in BBB integrity was attenuated by aging or when cognitive decline occurred, but the difference remained in the occipital cortex independently of these two factors [138].
Although currently few studies in the literature have analysed MMPs as a function of sex in patients affected by neurological disorders, some interesting data have already emerged.
Reduced serum levels of MMP-1 were found in PD patients in comparison to controls, and this difference was more evident in females [139]. On the contrary, CSF levels of MMP-1 were higher in females than in males in people with MS and neurological controls [140].
While high levels of MMP-3 appear to be more associated with male sex in AD patients in two studies [141,142], an increase in MMP-3 was associated with greater cognitive impairment in females [141]. Moreover, serum levels of MMP-3 were higher in male subjects with epilepsy with respect to females [143].
High levels of serum MMP-9 were more likely found in male subjects during the acute phase of ischemic stroke and were associated with an increased risk of major disability and death [144].
Sex-specific patterns of MMP expression were described in the days following intracerebral haemorrhage; in particular, MMP-3 and MMP-10 acted as predictors of long-term functional outcomes in male and female patients, respectively [145].
Finally, higher CSF MMP-10 levels were found in female than in male MS patients [140].
Sex-related differences in MMPs in patients affected by CNS disorders are summarized in Table 4.

5. Conclusions

The importance of studying sex differences lies in the fact that they are an important factor contributing to individual differences. This stemmed from several epidemiological and observational studies, including those on cardiovascular and neurological disorders. For instance, males have a higher incidence of stroke across much of their lifespan, but after 80 years of age, the situation is reversed, disadvantaging females. Keeping stroke as an example, symptoms might be sex-specific, and the type of stroke might occur with a sex bias. Therefore, in this current era of precision medicine, it is of paramount importance to consider sex differences not only related to aetiology but also at the biomarkers’ level.
In fact, from what we found (see Figure 5 for a summary), there is a clear disparity between males and females in MMP levels in several disorders. However, it is important to acknowledge that in a large part of the studies, sex has typically been considered a confounding factor used to correct statistical models to solely relate the biomarkers to the disease. As such, sex-specific differences have not been examined, eliminating part of the biological information that might help in identifying novel disease patterns or new sex-specific disease biomarkers. Therefore, it is compelling to evaluate sex differences in each study, especially considering that just because a difference is not apparent, it does not mean that is not visible. More importantly, sex differences should be studied across the lifespan of individuals.
Thus, the consideration of sex differences in MMPs and more in general in biofluid-based biomarkers is important and timely for their future application to clinical practice.
Therefore, a systematic disaggregation and analysis of data by sex may shed light on the possible use of MMPs as sex-specific biomarkers of disease prognosis and progression.

Author Contributions

Conceptualization, T.B.; writing—original draft preparation, A.T., M.C.M, and M.C.; writing—review and editing, A.T., M.C.M., and M.C.; supervision, T.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding. The APC was funded by University Center for Studies on Gender Medicine.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data used for this study are publicly available to download from https://vizhub.healthdata.org/gbd-results/.

Acknowledgments

This study was supported by the University Center for Studies on Gender Medicine, University of Ferrara. We thank Davide Lanzoni and Sara Trentini for their support in preparing the pictures.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ngun, T.C.; Ghahramani, N.; Sánchez, F.J.; Bocklandt, S.; Vilain, E. The Genetics of Sex Differences in Brain and Behavior. Front. Neuroendocrinol. 2011, 32, 227–246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. McGregor, A.J.; Hasnain, M.; Sandberg, K.; Morrison, M.F.; Berlin, M.; Trott, J. How to Study the Impact of Sex and Gender in Medical Research: A Review of Resources. Biol. Sex Differ. 2016, 7, 46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Oertelt-Prigione, S.; Dalibert, L.; Verdonk, P.; Stutz, E.Z.; Klinge, I. Implementation Strategies for Gender-Sensitive Public Health Practice: A European Workshop. J. Women’s Health 2017, 26, 1255–1261. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Gemmati, D.; Varani, K.; Bramanti, B.; Piva, R.; Bonaccorsi, G.; Trentini, A.; Manfrinato, M.C.; Tisato, V.; Carè, A.; Bellini, T. “Bridging the Gap” Everything That Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era. Int. J. Mol. Sci. 2019, 21, 296. [Google Scholar] [CrossRef] [Green Version]
  5. Feigin, V.L.; Vos, T. Global Burden of Neurological Disorders: From Global Burden of Disease Estimates to Actions. Neuroepidemiology 2019, 52, 1–2. [Google Scholar] [CrossRef] [PubMed]
  6. Chapman, N.; Thomas, E.E.; Tan, J.T.M.; Inglis, S.C.; Wu, J.H.Y.; Climie, R.E.; Picone, D.S.; Blekkenhorst, L.C.; Wise, S.G.; Mirabito Colafella, K.M.; et al. A Roadmap of Strategies to Support Cardiovascular Researchers: From Policy to Practice. Nat. Rev. Cardiol. 2022. online ahead of print. [Google Scholar] [CrossRef]
  7. Ramsey, J.M.; Cooper, J.D.; Penninx, B.W.J.H.; Bahn, S. Variation in Serum Biomarkers with Sex and Female Hormonal Status: Implications for Clinical Tests. Sci. Rep. 2016, 6, 26947. [Google Scholar] [CrossRef]
  8. Chhabra, A.; Kohli, S.; Rani, V. MMPs in Cardiovascular Diseases: Emerging Pharmacological Targets. In Role of Proteases in Cellular Dysfunction; Springer: New York, NY, USA, 2014; pp. 407–426. [Google Scholar]
  9. Rosenberg, G. Metalloproteinases and Neurodegenerative Diseases: Pathophysiological and Therapeutic Perspectives. Metalloproteinases Med. 2015, 2, 39–50. [Google Scholar] [CrossRef] [Green Version]
  10. Rempe, R.G.; Hartz, A.M.S.; Bauer, B. Matrix Metalloproteinases in the Brain and Blood-Brain Barrier: Versatile Breakers and Makers. J. Cereb. Blood Flow Metab. 2016, 36, 1481–1507. [Google Scholar] [CrossRef] [Green Version]
  11. Zhang, Q.; Zheng, M.; Betancourt, C.E.; Liu, L.; Sitikov, A.; Sladojevic, N.; Zhao, Q.; Zhang, J.H.; Liao, J.K.; Wu, R. Increase in Blood-Brain Barrier (BBB) Permeability Is Regulated by MMP3 via the ERK Signaling Pathway. Oxid. Med. Cell. Longev. 2021, 2021, 6655122. [Google Scholar] [CrossRef]
  12. Olejarz, W.; Łacheta, D.; Kubiak-Tomaszewska, G. Matrix Metalloproteinases as Biomarkers of Atherosclerotic Plaque Instability. Int. J. Mol. Sci. 2020, 21, 3946. [Google Scholar] [CrossRef] [PubMed]
  13. Thrailkill, K.M.; Moreau, C.S.; Cockrell, G.; Simpson, P.; Goel, R.; North, P.; Fowlkes, J.L.; Bunn, R.C. Physiological Matrix Metalloproteinase Concentrations in Serum during Childhood and Adolescence, Using Luminex Multiplex Technology. Clin. Chem. Lab. Med. 2005, 43, 1392–1399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. De Almeida, L.G.N.; Thode, H.; Eslambolchi, Y.; Chopra, S.; Young, D.; Gill, S.; Devel, L.; Dufour, A. Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology. Pharmacol. Rev. 2022, 74, 712–768. [Google Scholar] [CrossRef]
  15. Loffek, S.; Schilling, O.; Franzke, C.-W. Biological Role of Matrix Metalloproteinases: A Critical Balance. Eur. Respir. J. 2011, 38, 191–208. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Larsen, M.B.; Stephens, R.W.; Brünner, N.; Nielsen, H.J.; Engelholm, L.H.; Christensen, I.J.; Stetler-Stevenson, W.G.; Høyer-Hansen, G. Quantification of Tissue Inhibitor of Metalloproteinases 2 in Plasma from Healthy Donors and Cancer Patients. Scand. J. Immunol. 2005, 61, 449–460. [Google Scholar] [CrossRef]
  17. Burrage, P.S.; Mix, K.S.; Brinckerhoff, C.E. Matrix Metalloproteinases: Role in Arthritis. Front. Biosci. 2006, 11, 529–543. [Google Scholar] [CrossRef] [Green Version]
  18. Roldán, V.; Marín, F.; Gimeno, J.R.; Ruiz-Espejo, F.; González, J.; Feliu, E.; García-Honrubia, A.; Saura, D.; de la Morena, G.; Valdés, M.; et al. Matrix Metalloproteinases and Tissue Remodeling in Hypertrophic Cardiomyopathy. Am. Heart J. 2008, 156, 85–91. [Google Scholar] [CrossRef]
  19. Komosinska-Vassev, K.; Olczyk, P.; Winsz-Szczotka, K.; Kuznik-Trocha, K.; Klimek, K.; Olczyk, K. Age- and Gender-Dependent Changes in Connective Tissue Remodeling: Physiological Differences in Circulating MMP-3, MMP-10, TIMP-1 and TIMP-2 Level. Gerontology 2011, 57, 44–52. [Google Scholar] [CrossRef]
  20. Behl, T.; Kaur, G.; Sehgal, A.; Bhardwaj, S.; Singh, S.; Buhas, C.; Judea-Pusta, C.; Uivarosan, D.; Munteanu, M.A.; Bungau, S. Multifaceted Role of Matrix Metalloproteinases in Neurodegenerative Diseases: Pathophysiological and Therapeutic Perspectives. Int. J. Mol. Sci. 2021, 22, 1413. [Google Scholar] [CrossRef]
  21. Nagase, H.; Visse, R.; Murphy, G. Structure and Function of Matrix Metalloproteinases and TIMPs. Cardiovasc. Res. 2006, 69, 562–573. [Google Scholar] [CrossRef] [Green Version]
  22. Verma, R.P.; Hansch, C. Matrix Metalloproteinases (MMPs): Chemical-Biological Functions and (Q)SARs. Bioorg. Med. Chem. 2007, 15, 2223–2268. [Google Scholar] [CrossRef] [PubMed]
  23. Paiva, K.B.S.; Granjeiro, J.M. Bone Tissue Remodeling and Development: Focus on Matrix Metalloproteinase Functions. Arch. Biochem. Biophys. 2014, 561, 74–87. [Google Scholar] [CrossRef] [PubMed]
  24. Kapoor, C.; Vaidya, S.; Wadhwan, V.; Hitesh; Kaur, G.; Pathak, A. Seesaw of Matrix Metalloproteinases (MMPs). J. Cancer Res. Ther. 2016, 12, 28–35. [Google Scholar] [CrossRef]
  25. Jabłońska-Trypuć, A.; Matejczyk, M.; Rosochacki, S. Matrix Metalloproteinases (MMPs), the Main Extracellular Matrix (ECM) Enzymes in Collagen Degradation, as a Target for Anticancer Drugs. J. Enzyme. Inhib. Med. Chem. 2016, 31, 177–183. [Google Scholar] [CrossRef] [Green Version]
  26. van Wart, H.E.; Birkedal-Hansen, H. The Cysteine Switch: A Principle of Regulation of Metalloproteinase Activity with Potential Applicability to the Entire Matrix Metalloproteinase Gene Family. Proc. Natl. Acad. Sci. USA 1990, 87, 5578–5582. [Google Scholar] [CrossRef] [Green Version]
  27. Bode, W.; Gomis-Rüth, F.X.; Stöckler, W. Astacins, Serralysins, Snake Venom and Matrix Metalloproteinases Exhibit Identical Zinc-Binding Environments (HEXXHXXGXXH and Met-Turn) and Topologies and Should Be Grouped into a Common Family, the “Metzincins”. FEBS Lett. 1993, 331, 134–140. [Google Scholar] [CrossRef] [Green Version]
  28. Cui, N.; Hu, M.; Khalil, R.A. Biochemical and Biological Attributes of Matrix Metalloproteinases. Prog. Mol. Biol. Transl. Sci. 2017, 147, 1–73. [Google Scholar] [CrossRef] [Green Version]
  29. Jaoude, J.; Koh, Y. Matrix Metalloproteinases in Exercise and Obesity. Vasc Health Risk Manag 2016, 12, 287–295. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Eckhard, U.; Huesgen, P.F.; Schilling, O.; Bellac, C.L.; Butler, G.S.; Cox, J.H.; Dufour, A.; Goebeler, V.; Kappelhoff, R.; Keller, U.A.; et al. Active Site Specificity Profiling of the Matrix Metalloproteinase Family: Proteomic Identification of 4300 Cleavage Sites by Nine MMPs Explored with Structural and Synthetic Peptide Cleavage Analyses. Matrix Biol. 2016, 49, 37–60. [Google Scholar] [CrossRef]
  31. Ra, H.-J.; Parks, W.C. Control of Matrix Metalloproteinase Catalytic Activity. Matrix Biol. 2007, 26, 587–596. [Google Scholar] [CrossRef] [Green Version]
  32. Cauwe, B.; Opdenakker, G. Intracellular Substrate Cleavage: A Novel Dimension in the Biochemistry, Biology and Pathology of Matrix Metalloproteinases. Crit. Rev. Biochem. Mol. Biol. 2010, 45, 351–423. [Google Scholar] [CrossRef] [PubMed]
  33. Yan, C.; Boyd, D.D. Regulation of Matrix Metalloproteinase Gene Expression. J. Cell. Physiol. 2007, 211, 19–26. [Google Scholar] [CrossRef] [PubMed]
  34. Arpino, V.; Brock, M.; Gill, S.E. The Role of TIMPs in Regulation of Extracellular Matrix Proteolysis. Matrix Biol. 2015, 44, 247–254. [Google Scholar] [CrossRef] [PubMed]
  35. Roderfeld, M.; Graf, J.; Giese, B.; Salguero-Palacios, R.; Tschuschner, A.; Müller-Newen, G.; Roeb, E. Latent MMP-9 Is Bound to TIMP-1 before Secretion. BCHM 2007, 388, 1227–1234. [Google Scholar] [CrossRef]
  36. Ardi, V.C.; Kupriyanova, T.A.; Deryugina, E.I.; Quigley, J.P. Human Neutrophils Uniquely Release TIMP-Free MMP-9 to Provide a Potent Catalytic Stimulator of Angiogenesis. Proc. Natl Acad. Sci. USA 2007, 104, 20262–20267. [Google Scholar] [CrossRef] [Green Version]
  37. Bellini, T.; Trentini, A.; Manfrinato, M.C.; Tamborino, C.; Volta, C.A.; di Foggia, V.; Fainardi, E.; Dallocchio, F.; Castellazzi, M. Matrix Metalloproteinase-9 Activity Detected in Body Fluids Is the Result of Two Different Enzyme Forms. J. Biochem. 2012, 151, 493–499. [Google Scholar] [CrossRef]
  38. Trentini, A.; Manfrinato, M.C.; Castellazzi, M.; Tamborino, C.; Roversi, G.; Volta, C.A.; Baldi, E.; Tola, M.R.; Granieri, E.; Dallocchio, F.; et al. TIMP-1 Resistant Matrix Metalloproteinase-9 Is the Predominant Serum Active Isoform Associated with MRI Activity in Patients with Multiple Sclerosis. Mult. Scler. 2015, 21, 1121–1130. [Google Scholar] [CrossRef]
  39. Alfaddagh, A.; Martin, S.S.; Leucker, T.M.; Michos, E.D.; Blaha, M.J.; Lowenstein, C.J.; Jones, S.R.; Toth, P.P. Inflammation and Cardiovascular Disease: From Mechanisms to Therapeutics. Am. J. Prev. Cardiol. 2020, 4, 100130. [Google Scholar] [CrossRef]
  40. Shah, P.K.; Falk, E.; Badimon, J.J.; Fernandez-Ortiz, A.; Mailhac, A.; Villareal-Levy, G.; Fallon, J.T.; Regnstrom, J.; Fuster, V. Human Monocyte-Derived Macrophages Induce Collagen Breakdown in Fibrous Caps of Atherosclerotic Plaques. Potential Role of Matrix-Degrading Metalloproteinases and Implications for Plaque Rupture. Circulation 1995, 92, 1565–1569. [Google Scholar]
  41. Hopps, E.; lo Presti, R.; Caimi, G. Matrix Metalloproteases in Arterial Hypertension and Their Trend after Antihypertensive Treatment. Kidney Blood Press. Res. 2017, 42, 347–357. [Google Scholar] [CrossRef]
  42. Rizzi, E.; Castro, M.M.; Prado, C.M.; Silva, C.A.; Fazan, R.; Rossi, M.A.; Tanus-Santos, J.E.; Gerlach, R.F. Matrix Metalloproteinase Inhibition Improves Cardiac Dysfunction and Remodeling in 2-Kidney, 1-Clip Hypertension. J. Card. Fail. 2010, 16, 599–608. [Google Scholar] [CrossRef] [PubMed]
  43. Rodrigues, S.F.; Tran, E.D.; Fortes, Z.B.; Schmid-Schönbein, G.W. Matrix Metalloproteinases Cleave the β 2 -Adrenergic Receptor in Spontaneously Hypertensive Rats. Am. J. Physiol. Heart Circ. Physiol. 2010, 299, H25–H35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Fernandez-Patron, C.; Stewart, K.G.; Zhang, Y.; Koivunen, E.; Radomski, M.W.; Davidge, S.T. Vascular Matrix Metalloproteinase-2-Dependent Cleavage of Calcitonin Gene-Related Peptide Promotes Vasoconstriction. Circ. Res. 2000, 87, 670–676. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Martínez, A.; Oh, H.-R.; Unsworth, E.J.; Bregonzio, C.; Saavedra, J.M.; Stetler-Stevenson, W.G.; Cuttitta, F. Matrix Metalloproteinase-2 Cleavage of Adrenomedullin Produces a Vasoconstrictor out of a Vasodilator. Biochem. J. 2004, 383, 413–418. [Google Scholar] [CrossRef]
  46. Zhou, H.-Z.; Ma, X.; Gray, M.O.; Zhu, B.; Nguyen, A.P.; Baker, A.J.; Simonis, U.; Cecchini, G.; Lovett, D.H.; Karliner, J.S. Transgenic MMP-2 Expression Induces Latent Cardiac Mitochondrial Dysfunction. Biochem. Biophys. Res. Commun. 2007, 358, 189–195. [Google Scholar] [CrossRef] [Green Version]
  47. Sawicki, G.; Leon, H.; Sawicka, J.; Sariahmetoglu, M.; Schulze, C.J.; Scott, P.G.; Szczesna-Cordary, D.; Schulz, R. Degradation of Myosin Light Chain in Isolated Rat Hearts Subjected to Ischemia-Reperfusion Injury: A New Intracellular Target for Matrix Metalloproteinase-2. Circulation 2005, 112, 544–552. [Google Scholar] [CrossRef] [Green Version]
  48. Wang, W.; Schulze, C.J.; Suarez-Pinzon, W.L.; Dyck, J.R.B.; Sawicki, G.; Schulz, R. Intracellular Action of Matrix Metalloproteinase-2 Accounts for Acute Myocardial Ischemia and Reperfusion Injury. Circulation 2002, 106, 1543–1549. [Google Scholar] [CrossRef] [Green Version]
  49. Mata, K.M.; Prudente, P.S.; Rocha, F.S.; Prado, C.M.; Floriano, E.M.; Elias, J.; Rizzi, E.; Gerlach, R.F.; Rossi, M.A.; Ramos, S.G. Combining Two Potential Causes of Metalloproteinase Secretion Causes Abdominal Aortic Aneurysms in Rats: A New Experimental Model. Int. J. Exp. Pathol. 2011, 92, 26–39. [Google Scholar] [CrossRef]
  50. Knox, J.B.; Sukhova, G.K.; Whittemore, A.D.; Libby, P. Evidence for Altered Balance between Matrix Metalloproteinases and Their Inhibitors in Human Aortic Diseases. Circulation 1997, 95, 205–212. [Google Scholar] [CrossRef]
  51. Frangogiannis, N.G. Regulation of the Inflammatory Response in Cardiac Repair. Circ. Res. 2012, 110, 159–173. [Google Scholar] [CrossRef]
  52. Kai, H.; Ikeda, H.; Yasukawa, H.; Kai, M.; Seki, Y.; Kuwahara, F.; Ueno, T.; Sugi, K.; Imaizumi, T. Peripheral Blood Levels of Matrix Metalloproteases-2 and -9 Are Elevated in Patients with Acute Coronary Syndromes. J. Am. Coll. Cardiol. 1998, 32, 368–372. [Google Scholar] [CrossRef] [Green Version]
  53. Falk, E.; Shah, P.K.; Fuster, V. Coronary Plaque Disruption. Circulation 1995, 92, 657–671. [Google Scholar] [CrossRef] [PubMed]
  54. Wu, T.C.; Leu, H.B.; Lin, W.T.; Lin, C.P.; Lin, S.J.; Chen, J.W. Plasma Matrix Metalloproteinase-3 Level Is an Independent Prognostic Factor in Stable Coronary Artery Disease. Eur. J. Clin. Invest. 2005, 35, 537–545. [Google Scholar] [CrossRef] [PubMed]
  55. Kremastiotis, G.; Handa, I.; Jackson, C.; George, S.; Johnson, J. Disparate Effects of MMP and TIMP Modulation on Coronary Atherosclerosis and Associated Myocardial Fibrosis. Sci. Rep. 2021, 11, 1–16. [Google Scholar] [CrossRef]
  56. Lenglet, S.; Mach, F.; Montecucco, F. Role of Matrix Metalloproteinase-8 in Atherosclerosis. Mediat. Inflamm. 2013, 2013, 659282. [Google Scholar] [CrossRef] [Green Version]
  57. Mukherjee, R.; Mingoia, J.T.; Bruce, J.A.; Austin, J.S.; Stroud, R.E.; Escobar, G.P.; McClister, D.M.; Allen, C.M.; Alfonso-Jaume, M.A.; Fini, M.E.; et al. Selective Spatiotemporal Induction of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 Transcription after Myocardial Infarction. Am. J. Physiol. Heart Circ. Physiol. 2006, 291, H2216–H2228. [Google Scholar] [CrossRef] [Green Version]
  58. Ducharme, A.; Frantz, S.; Aikawa, M.; Rabkin, E.; Lindsey, M.; Rohde, L.E.; Schoen, F.J.; Kelly, R.A.; Werb, Z.; Libby, P.; et al. Targeted Deletion of Matrix Metalloproteinase-9 Attenuates Left Ventricular Enlargement and Collagen Accumulation after Experimental Myocardial Infarction. J. Clin. Invest. 2000, 106, 55–62. [Google Scholar] [CrossRef]
  59. Nilsson, L.; Hallén, J.; Atar, D.; Jonasson, L.; Swahn, E. Early Measurements of Plasma Matrix Metalloproteinase-2 Predict Infarct Size and Ventricular Dysfunction in ST-Elevation Myocardial Infarction. Heart 2012, 98, 31–36. [Google Scholar] [CrossRef]
  60. Kelly, D.; Cockerill, G.; Ng, L.L.; Thompson, M.; Khan, S.; Samani, N.J.; Squire, I.B. Plasma Matrix Metalloproteinase-9 and Left Ventricular Remodelling after Acute Myocardial Infarction in Man: A Prospective Cohort Study. Eur. Heart J. 2007, 28, 711–718. [Google Scholar] [CrossRef] [Green Version]
  61. Mukherjee, R.; Brinsa, T.A.; Dowdy, K.B.; Scott, A.A.; Baskin, J.M.; Deschamps, A.M.; Lowry, A.S.; Escobar, G.P.; Lucas, D.G.; Yarbrough, W.M.; et al. Myocardial Infarct Expansion and Matrix Metalloproteinase Inhibition. Circulation 2003, 107, 618–625. [Google Scholar] [CrossRef] [Green Version]
  62. Spinale, F.G.; Janicki, J.S.; Zile, M.R. Membrane-Associated Matrix Proteolysis and Heart Failure. Circ. Res. 2013, 112, 195–208. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Lijnen, H.R.; van Hoef, B.; Vanlinthout, I.; Verstreken, M.; Rio, M.C.; Collen, D. Accelerated Neointima Formation after Vascular Injury in Mice with Stromelysin-3 (MMP-11) Gene Inactivation. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 2863–2870. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Söder, P.-O.; Meurman, J.H.; Jogestrand, T.; Nowak, J.; Söder, B. Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 in Blood as Markers for Early Atherosclerosis in Subjects with Chronic Periodontitis. J. Periodontal Res. 2009, 44, 452–458. [Google Scholar] [CrossRef] [PubMed]
  65. Castro, M.M.; Rizzi, E.; Rodrigues, G.J.; Ceron, C.S.; Bendhack, L.M.; Gerlach, R.F.; Tanus-Santos, J.E. Antioxidant Treatment Reduces Matrix Metalloproteinase-2-Induced Vascular Changes in Renovascular Hypertension. Free Radic. Biol. Med. 2009, 46, 1298–1307. [Google Scholar] [CrossRef] [PubMed]
  66. Ceron, C.S.; Rizzi, E.; Guimaraes, D.A.; Martins-Oliveira, A.; Cau, S.B.; Ramos, J.; Gerlach, R.F.; Tanus-Santos, J.E. Time Course Involvement of Matrix Metalloproteinases in the Vascular Alterations of Renovascular Hypertension. Matrix Biol. 2012, 31, 261–270. [Google Scholar] [CrossRef]
  67. Fernandez-Patron, C.; Radomski, M.W.; Davidge, S.T. Vascular Matrix Metalloproteinase-2 Cleaves Big Endothelin-1 Yielding a Novel Vasoconstrictor. Circ. Res. 1999, 85, 906–911. [Google Scholar] [CrossRef]
  68. Matsusaka, H.; Ide, T.; Matsushima, S.; Ikeuchi, M.; Kubota, T.; Sunagawa, K.; Kinugawa, S.; Tsutsui, H. Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice with Chronic Pressure Overload. Hypertension 2006, 47, 711–717. [Google Scholar] [CrossRef] [Green Version]
  69. Agrawal, S.M.; Lau, L.; Yong, V.W. MMPs in the Central Nervous System: Where the Good Guys Go Bad. Semin. Cell Dev. Biol. 2008, 19, 42–51. [Google Scholar] [CrossRef]
  70. Lopez-Navarro, E.R.; Gutierrez, J. Metalloproteinases and Their Inhibitors in Neurological Disease. Naunyn Schmiedebergs Arch. Pharmacol. 2022, 395, 27–38. [Google Scholar] [CrossRef]
  71. Gasche, Y.; Soccal, P.M.; Kanemitsu, M.; Copin, J.-C. Matrix Metalloproteinases and Diseases of the Central Nervous System with a Special Emphasis on Ischemic Brain. Front. Biosci. 2006, 11, 1289–1301. [Google Scholar] [CrossRef] [Green Version]
  72. Newby, A.C. Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture. Physiol. Rev. 2005, 85, 1–31. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Arend, W.P.; Dayer, J.M. Inhibition of the Production and Effects of Interleukin-1 and Tumor Necrosis Factor Alpha in Rheumatoid Arthritis. Arthritis Rheum. 1995, 38, 151–160. [Google Scholar] [CrossRef] [PubMed]
  74. Rosenberg, G.A. Matrix Metalloproteinases and Their Multiple Roles in Neurodegenerative Diseases. Lancet Neurol. 2009, 8, 205–216. [Google Scholar] [CrossRef]
  75. Candelario-Jalil, E.; Yang, Y.; Rosenberg, G.A. Diverse Roles of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Neuroinflammation and Cerebral Ischemia. Neuroscience 2009, 158, 983–994. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Wang, X.-X.; Tan, M.-S.; Yu, J.-T.; Tan, L. Matrix Metalloproteinases and Their Multiple Roles in Alzheimer’s Disease. Biomed. Res. Int. 2014, 2014, 908636. [Google Scholar] [CrossRef]
  77. Fainardi, E.; Castellazzi, M.; Tamborino, C.; Trentini, A.; Manfrinato, M.C.; Baldi, E.; Tola, M.R.; Dallocchio, F.; Granieri, E.; Bellini, T. Potential Relevance of Cerebrospinal Fluid and Serum Levels and Intrathecal Synthesis of Active Matrix Metalloproteinase-2 (MMP-2) as Markers of Disease Remission in Patients with Multiple Sclerosis. Mult. Scler. 2009, 15, 547–554. [Google Scholar] [CrossRef]
  78. Choi, D.H.; Kim, E.-M.; Son, H.J.; Joh, T.H.; Kim, Y.S.; Kim, D.; Flint Beal, M.; Hwang, O. A Novel Intracellular Role of Matrix Metalloproteinase-3 during Apoptosis of Dopaminergic Cells. J. Neurochem. 2008, 106, 405–415. [Google Scholar] [CrossRef]
  79. Powell, B.S.; Dhaher, Y.Y.; Szleifer, I.G. Review of the Multiscale Effects of Female Sex Hormones on Matrix Metalloproteinase-Mediated Collagen Degradation. Crit. Rev. Biomed. Eng. 2015, 43, 401–428. [Google Scholar] [CrossRef]
  80. Fainardi, E.; Castellazzi, M.; Bellini, T.; Manfrinato, M.C.; Baldi, E.; Casetta, I.; Paolino, E.; Granieri, E.; Dallocchio, F. Cerebrospinal Fluid and Serum Levels and Intrathecal Production of Active Matrix Metalloproteinase-9 (MMP-9) as Markers of Disease Activity in Patients with Multiple Sclerosis. Mult. Scler. 2006, 12, 294–301. [Google Scholar] [CrossRef]
  81. Bjerke, M.; Zetterberg, H.; Edman, Å.; Blennow, K.; Wallin, A.; Andreasson, U. Cerebrospinal Fluid Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Combination with Subcortical and Cortical Biomarkers in Vascular Dementia and Alzheimer’s Disease. J. Alzheimers Dis. 2011, 27, 665–676. [Google Scholar] [CrossRef]
  82. Gutierrez, J.; Menshawy, K.; Goldman, J.; Dwork, A.J.; Elkind, M.S.V.; Marshall, R.S.; Morgello, S. Metalloproteinases and Brain Arterial Remodeling Among Individuals with and Those Without HIV Infection. J. Infect. Dis. 2016, 214, 1329–1335. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Gutierrez, J.; Sacco, R.L.; Wright, C.B. Dolichoectasia-an Evolving Arterial Disease. Nat. Rev. Neurol. 2011, 7, 41–50. [Google Scholar] [CrossRef] [PubMed]
  84. Kiaei, M.; Kipiani, K.; Calingasan, N.Y.; Wille, E.; Chen, J.; Heissig, B.; Rafii, S.; Lorenzl, S.; Beal, M.F. Matrix Metalloproteinase-9 Regulates TNF-Alpha and FasL Expression in Neuronal, Glial Cells and Its Absence Extends Life in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. Exp. Neurol. 2007, 205, 74–81. [Google Scholar] [CrossRef]
  85. Kaplan, A.; Spiller, K.J.; Towne, C.; Kanning, K.C.; Choe, G.T.; Geber, A.; Akay, T.; Aebischer, P.; Henderson, C.E. Neuronal Matrix Metalloproteinase-9 Is a Determinant of Selective Neurodegeneration. Neuron 2014, 81, 333–348. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Miller, J.P.; Holcomb, J.; Al-Ramahi, I.; de Haro, M.; Gafni, J.; Zhang, N.; Kim, E.; Sanhueza, M.; Torcassi, C.; Kwak, S.; et al. Matrix Metalloproteinases Are Modifiers of Huntingtin Proteolysis and Toxicity in Huntington’s Disease. Neuron 2010, 67, 199–212. [Google Scholar] [CrossRef] [Green Version]
  87. Rosenberg, G.A. Extracellular Matrix Inflammation in Vascular Cognitive Impairment and Dementia. Clin. Sci. 2017, 131, 425–437. [Google Scholar] [CrossRef]
  88. Lech, A.M.; Wiera, G.; Mozrzymas, J.W. Matrix Metalloproteinase-3 in Brain Physiology and Neurodegeneration. Adv. Clin. Exp. Med. 2019, 28, 1717–1722. [Google Scholar] [CrossRef]
  89. Mikkola, T.S.; Gissler, M.; Merikukka, M.; Tuomikoski, P.; Ylikorkala, O. Sex Differences in Age-Related Cardiovascular Mortality. PLoS ONE 2013, 8, e63347. [Google Scholar] [CrossRef] [Green Version]
  90. Bergeron, A.; Hertig, V.; Villeneuve, L.; Chauvette, V.; El-Hamamsy, I.; Calderone, A. The Ascending Aorta of Male Hypertensive Bicuspid Aortic Valve Patients Preferentially Associated with a Cellular Aneurysmal Phenotype. Physiol. Rep. 2022, 10, e15251. [Google Scholar] [CrossRef]
  91. DiMusto, P.D.; Lu, G.; Ghosh, A.; Roelofs, K.J.; Sadiq, O.; McEvoy, B.; Su, G.; Laser, A.; Bhamidipati, C.M.; Ailawadi, G.; et al. Increased JNK in Males Compared with Females in a Rodent Model of Abdominal Aortic Aneurysm. J. Surg. Res. 2012, 176, 687–695. [Google Scholar] [CrossRef] [Green Version]
  92. Ehrlichman, L.K.; Ford, J.W.; Roelofs, K.J.; Tedeschi-Filho, W.; Futchko, J.S.; Ramacciotti, E.; Eliason, J.L.; Henke, P.K.; Upchurch, G.R. Gender-Dependent Differential Phosphorylation in the ERK Signaling Pathway Is Associated with Increased MMP2 Activity in Rat Aortic Smooth Muscle Cells. J. Surg. Res. 2010, 160, 18–24. [Google Scholar] [CrossRef] [Green Version]
  93. Sokolis, D.P.; Iliopoulos, D.C. Impaired Mechanics and Matrix Metalloproteinases/Inhibitors Expression in Female Ascending Thoracic Aortic Aneurysms. J. Mech. Behav. Biomed. Mater. 2014, 34, 154–164. [Google Scholar] [CrossRef] [PubMed]
  94. Lee, J.; Shen, M.; Parajuli, N.; Oudit, G.Y.; McMurtry, M.S.; Kassiri, Z. Gender-Dependent Aortic Remodelling in Patients with Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm. J. Mol. Med. (Berl.) 2014, 92, 939–949. [Google Scholar] [CrossRef] [PubMed]
  95. Holmes, K.W.; Maslen, C.L.; Kindem, M.; Kroner, B.L.; Song, H.K.; Ravekes, W.; Dietz, H.C.; Weinsaft, J.W.; Roman, M.J.; Devereux, R.B.; et al. GenTAC Registry Report: Gender Differences among Individuals with Genetically Triggered Thoracic Aortic Aneurysm and Dissection. Am. J. Med. Genet. 2013, 161, 779–786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Maguire, E.M.; Pearce, S.W.A.; Xiao, R.; Oo, A.Y.; Xiao, Q. Matrix Metalloproteinase in Abdominal Aortic Aneurysm and Aortic Dissection. Pharmaceuticals 2019, 12, 118. [Google Scholar] [CrossRef] [Green Version]
  97. Cavasin, M.A.; Tao, Z.; Menon, S.; Yang, X.-P. Gender Differences in Cardiac Function during Early Remodeling after Acute Myocardial Infarction in Mice. Life Sci. 2004, 75, 2181–2192. [Google Scholar] [CrossRef]
  98. Münch, J.; Avanesov, M.; Bannas, P.; Säring, D.; Krämer, E.; Mearini, G.; Carrier, L.; Suling, A.; Lund, G.; Patten, M. Serum Matrix Metalloproteinases as Quantitative Biomarkers for Myocardial Fibrosis and Sudden Cardiac Death Risk Stratification in Patients With Hypertrophic Cardiomyopathy. J. Card. Fail. 2016, 22, 845–850. [Google Scholar] [CrossRef]
  99. Samnegård, A.; Silveira, A.; Tornvall, P.; Hamsten, A.; Ericsson, C.-G.; Eriksson, P. Lower Serum Concentration of Matrix Metalloproteinase-3 in the Acute Stage of Myocardial Infarction. J. Intern. Med. 2006, 259, 530–536. [Google Scholar] [CrossRef]
  100. Samnegård, A.; Silveira, A.; Lundman, P.; Boquist, S.; Odeberg, J.; Hulthe, J.; McPheat, W.; Tornvall, P.; Bergstrand, L.; Ericsson, C.-G.; et al. Serum Matrix Metalloproteinase-3 Concentration Is Influenced by MMP-3 -1612 5A/6A Promoter Genotype and Associated with Myocardial Infarction. J. Intern. Med. 2005, 258, 411–419. [Google Scholar] [CrossRef]
  101. Samnegård, A.; Hulthe, J.; Silveira, A.; Ericsson, C.-G.; Hamsten, A.; Eriksson, P. Gender Specific Associations between Matrix Metalloproteinases and Inflammatory Markers in Post Myocardial Infarction Patients. Atherosclerosis 2009, 202, 550–556. [Google Scholar] [CrossRef]
  102. Hellings, W.E.; Pasterkamp, G.; Verhoeven, B.A.N.; de Kleijn, D.P.V.; de Vries, J.-P.P.M.; Seldenrijk, K.A.; van den Broek, T.; Moll, F.L. Gender-Associated Differences in Plaque Phenotype of Patients Undergoing Carotid Endarterectomy. J. Vasc. Surg. 2007, 45, 289–296, discussion 296-7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Djurić, T.; Zivković, M.; Stanković, A.; Kolaković, A.; Jekić, D.; Selaković, V.; Alavantić, D. Plasma Levels of Matrix Metalloproteinase-8 in Patients with Carotid Atherosclerosis. J. Clin. Lab. Anal. 2010, 24, 246–251. [Google Scholar] [CrossRef] [PubMed]
  104. Bloomer, L.D.S.; Bown, M.J.; Tomaszewski, M. Sexual Dimorphism of Abdominal Aortic Aneurysms: A Striking Example of “Male Disadvantage” in Cardiovascular Disease. Atherosclerosis 2012, 225, 22–28. [Google Scholar] [CrossRef] [PubMed]
  105. Yabluchanskiy, A.; Ma, Y.; Iyer, R.P.; Hall, M.E.; Lindsey, M.L. Matrix Metalloproteinase-9: Many Shades of Function in Cardiovascular Disease. Physiology 2013, 28, 391–403. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Ailawadi, G.; Eliason, J.L.; Roelofs, K.J.; Sinha, I.; Hannawa, K.K.; Kaldjian, E.P.; Lu, G.; Henke, P.K.; Stanley, J.C.; Weiss, S.J.; et al. Gender Differences in Experimental Aortic Aneurysm Formation. Arterioscler. Thromb. Vasc. Biol. 2004, 24, 2116–2122. [Google Scholar] [CrossRef] [Green Version]
  107. Wang, F.; Keimig, T.; He, Q.; Ding, J.; Zhang, Z.; Pourabdollah-Nejad, S.; Yang, X.-P. Augmented Healing Process in Female Mice with Acute Myocardial Infarction. Gend. Med. 2007, 4, 230–247. [Google Scholar] [CrossRef]
  108. Fang, L.; Gao, X.-M.; Moore, X.-L.; Kiriazis, H.; Su, Y.; Ming, Z.; Lim, Y.L.; Dart, A.M.; Du, X.-J. Differences in Inflammation, MMP Activation and Collagen Damage Account for Gender Difference in Murine Cardiac Rupture Following Myocardial Infarction. J. Mol. Cell Cardiol. 2007, 43, 535–544. [Google Scholar] [CrossRef]
  109. Garvin, P.; Jonasson, L.; Nilsson, L.; Falk, M.; Kristenson, M. Plasma Matrix Metalloproteinase-9 Levels Predict First-Time Coronary Heart Disease: An 8-Year Follow-Up of a Community-Based Middle Aged Population. PLoS ONE 2015, 10, e0138290. [Google Scholar] [CrossRef]
  110. Kobayashi, N.; Hata, N.; Kume, N.; Yokoyama, S.; Shinada, T.; Tomita, K.; Kitamura, M.; Shirakabe, A.; Inami, T.; Yamamoto, M.; et al. Matrix Metalloproteinase-9 for the Earliest Stage Acute Coronary Syndrome. Circ. J. 2011, 75, 2853–2861. [Google Scholar] [CrossRef] [Green Version]
  111. Tayebjee, M.H.; Lip, G.Y.H.; Tan, K.T.; Patel, J.V.; Hughes, E.A.; MacFadyen, R.J. Plasma Matrix Metalloproteinase-9, Tissue Inhibitor of Metalloproteinase-2, and CD40 Ligand Levels in Patients with Stable Coronary Artery Disease. Am. J. Cardiol. 2005, 96, 339–345. [Google Scholar] [CrossRef]
  112. Sullivan, S.; Hammadah, M.; Wilmot, K.; Ramadan, R.; Pearce, B.D.; Shah, A.; Kaseer, B.; Gafeer, M.M.; Lima, B.B.; Kim, J.H.; et al. Young Women With Coronary Artery Disease Exhibit Higher Concentrations of Interleukin-6 at Baseline and in Response to Mental Stress. J. Am. Heart Assoc. 2018, 7, e010329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Cho, B.S.; Roelofs, K.J.; Ford, J.W.; Henke, P.K.; Upchurch, G.R. Decreased Collagen and Increased Matrix Metalloproteinase-13 in Experimental Abdominal Aortic Aneurysms in Males Compared with Females. Surgery 2010, 147, 258–267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Coronado, M.J.; Brandt, J.E.; Kim, E.; Bucek, A.; Bedja, D.; Abston, E.D.; Shin, J.; Gabrielson, K.L.; Mitzner, W.; Fairweather, D. Testosterone and Interleukin-1β Increase Cardiac Remodeling during Coxsackievirus B3 Myocarditis via Serpin A 3n. Am. J. Physiol. Heart Circ. Physiol. 2012, 302, H1726–H1736. [Google Scholar] [CrossRef] [PubMed]
  115. Passos, L.S.A.; Becker-Greene, D.; Braulio, R.; Le, T.-D.; Gelape, C.L.; de Almeida, L.F.R.; Rocha, D.P.A.; Gomes, C.A.P.; Esteves, W.A.M.; Passaglia, L.G.; et al. Proinflammatory Matrix Metalloproteinase-1 Associates with Mitral Valve Leaflet Disruption Following Percutaneous Mitral Valvuloplasty. Front. Cardiovasc. Med. 2021, 8, 804111. [Google Scholar] [CrossRef]
  116. Banerjee, T.; Mukherjee, S.; Ghosh, S.; Biswas, M.; Dutta, S.; Pattari, S.; Chatterjee, S.; Bandyopadhyay, A. Clinical Significance of Markers of Collagen Metabolism in Rheumatic Mitral Valve Disease. PLoS ONE 2014, 9, e90527. [Google Scholar] [CrossRef]
  117. Elhewala, A.A.; Sanad, M.; Soliman, A.M.; Sami, M.M.; Ahmed, A.A. Matrix Metalloproteinase-9 in Pediatric Rheumatic Heart Disease with and without Heart Failure. Biomed. Rep. 2021, 14, 4. [Google Scholar] [CrossRef]
  118. Lee, S.-D.; Chen, L.-M.; Kuo, W.-W.; Shu, W.-T.; Kuo, W.-H.; Huang, E.-J.; Tsai, C.-C.; Li, P.-C.; Liu, J.-Y.; Chen, T.-H.; et al. Serum Insulin-like Growth Factor-Axis and Matrix Metalloproteinases in Patients with Rheumatic Arthritis or Rheumatic Heart Disease. Clin. Chim. Acta. 2006, 367, 62–68. [Google Scholar] [CrossRef]
  119. Giannakos, E.; Vardali, E.; Bartekova, M.; Fogarassyova, M.; Barancik, M.; Radosinska, J. Changes in Activities of Circulating MMP-2 and MMP-9 in Patients Suffering from Heart Failure in Relation to Gender, Hypertension and Treatment: A Cross-Sectional Study. Physiol. Res. 2016, 65, S149. [Google Scholar] [CrossRef]
  120. Mendes, P.R.; Kiyota, T.A.; Cipolli, J.A.; Schreiber, R.; Paim, L.R.; Bellinazzi, V.R.; Matos-Souza, J.R.; Sposito, A.C.; Nadruz, W. Gender Influences the Relationship between Lung Function and Cardiac Remodeling in Hypertensive Subjects. Hypertens. Res. 2015, 38, 264–268. [Google Scholar] [CrossRef]
  121. Ramani, R.; Mathier, M.; Wang, P.; Gibson, G.; Tögel, S.; Dawson, J.; Bauer, A.; Alber, S.; Watkins, S.C.; McTiernan, C.F.; et al. Inhibition of Tumor Necrosis Factor Receptor-1-Mediated Pathways Has Beneficial Effects in a Murine Model of Postischemic Remodeling. Am. J. Physiol. Heart Circ. Physiol. 2004, 287, H1369–H1377. [Google Scholar] [CrossRef]
  122. Gu, C.; Wang, F.; Hou, Z.; Lv, B.; Wang, Y.; Cong, X.; Chen, X. Sex-Related Differences in Serum Matrix Metalloproteinase-9 Screening Non-Calcified and Mixed Coronary Atherosclerotic Plaques in Outpatients with Chest Pain. Heart Vessel. 2017, 32, 1424–1431. [Google Scholar] [CrossRef] [PubMed]
  123. Goldstein, J.M. Normal Sexual Dimorphism of the Adult Human Brain Assessed by In Vivo Magnetic Resonance Imaging. Cereb. Cortex 2001, 11, 490–497. [Google Scholar] [CrossRef] [PubMed]
  124. Nishizawa, S.; Benkelfat, C.; Young, S.N.; Leyton, M.; Mzengeza, S.; de Montigny, C.; Blier, P.; Diksic, M. Differences between Males and Females in Rates of Serotonin Synthesis in Human Brain. Proc. Natl. Acad. Sci. USA 1997, 94, 5308–5313. [Google Scholar] [CrossRef] [Green Version]
  125. Feng, B.; Cao, J.; Yu, Y.; Yang, H.; Jiang, Y.; Liu, Y.; Wang, R.; Zhao, Q. Gender-Related Differences in Regional Cerebral Glucose Metabolism in Normal Aging Brain. Front. Aging Neurosci. 2022, 14, 809767. [Google Scholar] [CrossRef] [PubMed]
  126. Gur, R.C.; Gur, R.E. Complementarity of Sex Differences in Brain and Behavior: From Laterality to Multimodal Neuroimaging. J. Neurosci. Res. 2017, 95, 189–199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. The Lancet Neurology A Spotlight on Sex Differences in Neurological Disorders. Lancet Neurol. 2019, 18, 319. [CrossRef]
  128. Wooten, G.F. Are Men at Greater Risk for Parkinson’s Disease than Women? J. Neurol. Neurosurg. Psychiatry 2004, 75, 637–639. [Google Scholar] [CrossRef]
  129. McHugh, J.C.; Delanty, N. Epidemiology and Classification of Epilepsy: Gender Comparisons. Int. Rev. Neurobiol. 2008, 83, 11–26. [Google Scholar] [CrossRef]
  130. Vyas, M.V.; Silver, F.L.; Austin, P.C.; Yu, A.Y.X.; Pequeno, P.; Fang, J.; Laupacis, A.; Kapral, M.K. Stroke Incidence by Sex Across the Lifespan. Stroke 2021, 52, 447–451. [Google Scholar] [CrossRef]
  131. Manjaly, Z.R.; Scott, K.M.; Abhinav, K.; Wijesekera, L.; Ganesalingam, J.; Goldstein, L.H.; Janssen, A.; Dougherty, A.; Willey, E.; Stanton, B.R.; et al. The Sex Ratio in Amyotrophic Lateral Sclerosis: A Population Based Study. Amyotroph. Lateral Scler. 2010, 11, 439–442. [Google Scholar] [CrossRef]
  132. Na, W.; Lee, J.Y.; Kim, W.-S.; Yune, T.Y.; Ju, B.-G. 17β-Estradiol Ameliorates Tight Junction Disruption via Repression of MMP Transcription. Mol. Endocrinol. 2015, 29, 1347–1361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Castellazzi, M.; Pizzicotti, S.; Lombardo, I.; Alfiero, S.; Morotti, A.; Pellegatti, P.; Negri, G.; Natali, L.; Ferri, C.; Fainardi, E.; et al. Sexual Dimorphism in the Cerebrospinal Fluid Total Protein Content. Clin. Chem. Lab. Med. 2020, 58, 1885–1890. [Google Scholar] [CrossRef] [PubMed]
  134. McCudden, C.R.; Brooks, J.; Figurado, P.; Bourque, P.R. Cerebrospinal Fluid Total Protein Reference Intervals Derived from 20 Years of Patient Data. Clin. Chem. 2017, 63, 1856–1865. [Google Scholar] [CrossRef] [PubMed]
  135. Castellazzi, M.; Morotti, A.; Tamborino, C.; Alessi, F.; Pilotto, S.; Baldi, E.; Caniatti, L.M.; Trentini, A.; Casetta, I.; Granieri, E.; et al. Increased Age and Male Sex Are Independently Associated with Higher Frequency of Blood-Cerebrospinal Fluid Barrier Dysfunction Using the Albumin Quotient. Fluids Barriers CNS 2020, 17, 14. [Google Scholar] [CrossRef]
  136. Meixensberger, S.; Bechter, K.; Dersch, R.; Feige, B.; Maier, S.; Schiele, M.A.; Runge, K.; Denzel, D.; Nickel, K.; Spieler, D.; et al. Sex Difference in Cerebrospinal Fluid/Blood Albumin Quotients in Patients with Schizophreniform and Affective Psychosis. Fluids Barriers CNS 2020, 17, 67. [Google Scholar] [CrossRef]
  137. Parrado-Fernández, C.; Blennow, K.; Hansson, M.; Leoni, V.; Cedazo-Minguez, A.; Björkhem, I. Evidence for Sex Difference in the CSF/Plasma Albumin Ratio in ~20 000 Patients and 335 Healthy Volunteers. J. Cell. Mol. Med. 2018, 22, 5151–5154. [Google Scholar] [CrossRef] [Green Version]
  138. Moon, Y.; Lim, C.; Kim, Y.; Moon, W.-J. Sex-Related Differences in Regional Blood-Brain Barrier Integrity in Non-Demented Elderly Subjects. Int. J. Mol. Sci. 2021, 22, 2860. [Google Scholar] [CrossRef]
  139. Gupta, V.; Singh, M.K.; Garg, R.K.; Pant, K.K.; Khattri, S. Evaluation of Peripheral Matrix Metalloproteinase-1 in Parkinson’s Disease: A Case-Control Study. Int. J. Neurosci. 2014, 124, 88–92. [Google Scholar] [CrossRef]
  140. Castellazzi, M.; Ligi, D.; Contaldi, E.; Quartana, D.; Fonderico, M.; Borgatti, L.; Bellini, T.; Trentini, A.; Granieri, E.; Fainardi, E.; et al. Multiplex Matrix Metalloproteinases Analysis in the Cerebrospinal Fluid Reveals Potential Specific Patterns in Multiple Sclerosis Patients. Front. Neurol. 2018, 9, 1080. [Google Scholar] [CrossRef]
  141. Iulita, M.F.; Ganesh, A.; Pentz, R.; Flores Aguilar, L.; Gubert, P.; Ducatenzeiler, A.; Christie, S.; Wilcock, G.K.; Cuello, A.C. Identification and Preliminary Validation of a Plasma Profile Associated with Cognitive Decline in Dementia and At-Risk Individuals: A Retrospective Cohort Analysis. J. Alzheimers Dis. 2019, 67, 327–341. [Google Scholar] [CrossRef]
  142. Pentz, R.; Iulita, M.F.; Mikutra-Cencora, M.; Ducatenzeiler, A.; Bennett, D.A.; Cuello, A.C. A New Role for Matrix Metalloproteinase-3 in the NGF Metabolic Pathway: Proteolysis of Mature NGF and Sex-Specific Differences in the Continuum of Alzheimer’s Pathology. Neurobiol. Dis. 2021, 148, 105150. [Google Scholar] [CrossRef] [PubMed]
  143. Wang, R.; Zeng, G.Q.; Liu, X.; Tong, R.Z.; Zhou, D.; Hong, Z. Evaluation of Serum Matrix Metalloproteinase-3 as a Biomarker for Diagnosis of Epilepsy. J. Neurol. Sci. 2016, 367, 291–297. [Google Scholar] [CrossRef] [PubMed]
  144. Zhong, C.; Yang, J.; Xu, T.; Xu, T.; Peng, Y.; Wang, A.; Wang, J.; Peng, H.; Li, Q.; Ju, Z.; et al. Serum Matrix Metalloproteinase-9 Levels and Prognosis of Acute Ischemic Stroke. Neurology 2017, 89, 805–812. [Google Scholar] [CrossRef] [PubMed]
  145. Howe, M.D.; Furr, J.W.; Zhu, L.; Edwards, N.J.; McCullough, L.D.; Gonzales, N.R. Sex-Specific Association of Matrix Metalloproteinases with Secondary Injury and Outcomes after Intracerebral Hemorrhage. J. Stroke Cerebrovasc. Dis. 2019, 28, 1718–1725. [Google Scholar] [CrossRef] [PubMed]
Jpm 12 01196 g001 550
Figure 1. Global estimates of disability-adjusted life-year (DALY) are disaggregated by sex for communicable diseases, non-communicable diseases, and injuries. Source: Global Burden of Disease Study 2019 (GBD 2019) (https://vizhub.healthdata.org/gbd-results/, accessed on 12 July 2022). Inf&Par, infectious and parasitic diseases; Resp inf, respiratory infectious; Mat Cond, maternal conditions; Neo Cond, neonatal conditions; Nut Def, nutritional deficiencies; Oth neop, other neoplasms; Diab, diabetes mellitus; End Bl Imm, endocrine, blood, immune disorders; Ment Sub, mental and substance use disorders; Neuro, neurological conditions; Sense, sense organ diseases; CVD, cardiovascular diseases; Resp, respiratory diseases; Dig, digestive disease; Gen, genitourinary diseases; Skin, skin diseases; Musc, musculoskeletal diseases; Cong, congenital diseases; Oral, oral conditions; Infant, sudden infant death syndrome; Un Inj, unintentional injuries; Int Inj, intentional injuries. Error bars represent the 95% uncertainty level (95% UL).
Figure 1. Global estimates of disability-adjusted life-year (DALY) are disaggregated by sex for communicable diseases, non-communicable diseases, and injuries. Source: Global Burden of Disease Study 2019 (GBD 2019) (https://vizhub.healthdata.org/gbd-results/, accessed on 12 July 2022). Inf&Par, infectious and parasitic diseases; Resp inf, respiratory infectious; Mat Cond, maternal conditions; Neo Cond, neonatal conditions; Nut Def, nutritional deficiencies; Oth neop, other neoplasms; Diab, diabetes mellitus; End Bl Imm, endocrine, blood, immune disorders; Ment Sub, mental and substance use disorders; Neuro, neurological conditions; Sense, sense organ diseases; CVD, cardiovascular diseases; Resp, respiratory diseases; Dig, digestive disease; Gen, genitourinary diseases; Skin, skin diseases; Musc, musculoskeletal diseases; Cong, congenital diseases; Oral, oral conditions; Infant, sudden infant death syndrome; Un Inj, unintentional injuries; Int Inj, intentional injuries. Error bars represent the 95% uncertainty level (95% UL).
Jpm 12 01196 g001
Jpm 12 01196 g002 550
Figure 2. Schematic structure of the major classes of MMPs. FR, fibronectin repeats; TMD, transmembrane domain; GPI, glycosylphosphatidylinositol. The structure of MMP-11 is similar to that of stromelysins except for a furin-like domain between the propeptide and the catalytic domain.
Figure 2. Schematic structure of the major classes of MMPs. FR, fibronectin repeats; TMD, transmembrane domain; GPI, glycosylphosphatidylinositol. The structure of MMP-11 is similar to that of stromelysins except for a furin-like domain between the propeptide and the catalytic domain.
Jpm 12 01196 g002
Jpm 12 01196 g003 550
Figure 3. Global estimates of disability-adjusted life-year (DALY) disaggregated by sex for cardiovascular diseases (CVDs). HD, heart disease; C.M.E., cardiomyopathy, myocarditis, endocarditis. Source: Global Burden of Disease Study 2019 (GBD 2019) (https://vizhub.healthdata.org/gbd-results/, accessed on 12 July 2022). Error bars represent the 95% uncertainty level (95% UL).
Figure 3. Global estimates of disability-adjusted life-year (DALY) disaggregated by sex for cardiovascular diseases (CVDs). HD, heart disease; C.M.E., cardiomyopathy, myocarditis, endocarditis. Source: Global Burden of Disease Study 2019 (GBD 2019) (https://vizhub.healthdata.org/gbd-results/, accessed on 12 July 2022). Error bars represent the 95% uncertainty level (95% UL).
Jpm 12 01196 g003
Jpm 12 01196 g004 550
Figure 4. Global estimates of disability-adjusted life-year (DALY) disaggregated by sex for neurological conditions. AD & Dement, Alzheimer’s disease AND other dementias; PD, Parkinson’s disease; MS, multiple sclerosis; St, stroke; N-M Head, non-migraine headache; Other, other neurological conditions. Source: (https://vizhub.healthdata.org/gbd-results/, accessed on 12 July 2022).
Figure 4. Global estimates of disability-adjusted life-year (DALY) disaggregated by sex for neurological conditions. AD & Dement, Alzheimer’s disease AND other dementias; PD, Parkinson’s disease; MS, multiple sclerosis; St, stroke; N-M Head, non-migraine headache; Other, other neurological conditions. Source: (https://vizhub.healthdata.org/gbd-results/, accessed on 12 July 2022).
Jpm 12 01196 g004
Jpm 12 01196 g005 550
Figure 5. Summary of the main changes in MMPs separated by sex and pathology. As pictured, on the top are represented the diseases more frequent in females, while on the bottom are listed those with an increased prevalence in males. To make the summary clearer, neurological conditions (right side, light salmon colour sector) are separated by CVDs (left side, light green sector). For instance, MS and AD, which are neurological conditions more frequent in females than males, are localized in the top right of the picture. While females with MS demonstrated to have increased levels of both MMP-1 and MMP-10, females with AD have lower levels of MMP-3. On the contrary, males with PD, stroke, and epilepsy (right bottom side), have higher levels of MMP-1, MMP-9, and MMP-3, respectively. The situation is different for CVDs, where there is a more male-driven sex disparity, with aneurysm, MI, and CAD more frequent in this sex (left bottom). As such, several MMPs have been found to increase in males affected by these conditions. Finally, although HHD and RHD seem to be more frequent in females (top left side), results about MMP levels are still lacking (question mark symbol). HHD, hypertensive heart disease; RHD, rheumatic heart disease; MS, multiple sclerosis; AD, Alzheimer’s disease; PD, Parkinson’s disease; CAD, coronary heart disease; MI, myocardial infarction.
Figure 5. Summary of the main changes in MMPs separated by sex and pathology. As pictured, on the top are represented the diseases more frequent in females, while on the bottom are listed those with an increased prevalence in males. To make the summary clearer, neurological conditions (right side, light salmon colour sector) are separated by CVDs (left side, light green sector). For instance, MS and AD, which are neurological conditions more frequent in females than males, are localized in the top right of the picture. While females with MS demonstrated to have increased levels of both MMP-1 and MMP-10, females with AD have lower levels of MMP-3. On the contrary, males with PD, stroke, and epilepsy (right bottom side), have higher levels of MMP-1, MMP-9, and MMP-3, respectively. The situation is different for CVDs, where there is a more male-driven sex disparity, with aneurysm, MI, and CAD more frequent in this sex (left bottom). As such, several MMPs have been found to increase in males affected by these conditions. Finally, although HHD and RHD seem to be more frequent in females (top left side), results about MMP levels are still lacking (question mark symbol). HHD, hypertensive heart disease; RHD, rheumatic heart disease; MS, multiple sclerosis; AD, Alzheimer’s disease; PD, Parkinson’s disease; CAD, coronary heart disease; MI, myocardial infarction.
Jpm 12 01196 g005
Table
Table 1. Matrix metalloproteinases (MMPs) that are mainly involved in cardiovascular diseases (CVDs).
Table 1. Matrix metalloproteinases (MMPs) that are mainly involved in cardiovascular diseases (CVDs).
MMPsCVDsRoleReferences
MMP-2HypertensionCauses vasoconstriction[41,42,43]
Limits vasodilation[44,45]
CardiomyopathiesIncreases infarct areas[46]
Process several cardiac proteins[47,48]
MMP-1, -2, -3, -8, and -9AneurismWeakens the ECM structure[49,50]
MMP-2 and -9Myocardial infarctionDegrade ECM/process cytokines and chemokines[51]
MMP-2, -3, -8, -9, and 12atherosclerosisconnected to plaque development[52,53,54,55,56]
MMP-7 and -9hypertensioncause vasoconstriction/increase blood pressure[43]
ECM, extracellular matrix.
Table
Table 2. Matrix metalloproteinases (MMPs) that are mainly involved in central nervous system (CNS) pathologies.
Table 2. Matrix metalloproteinases (MMPs) that are mainly involved in central nervous system (CNS) pathologies.
MMPsCNS ConditionsRoleReferences
MMP-2ADProtective[76]
MSAssociated to remission[77]
MMP-3AD and PDDetrimental[78,79]
MMP-9MSAssociated to demyelination[80]
ADAssociated to neuronal cell death[81]
PD and dolichoectasiaAssociated to neuroinflammation[20,82,83]
ALSAssociated to neuroinflammation[84,85]
MMP-10HDDetrimental[86]
MMP-2, -3, -9HI lesionsIncrease BBB permeability[74]
AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; BBB, blood–brain-barrier; HD, Huntington’s disease; HI, hypoxic ischemic; ICH, intracerebral haemorrhage; MS, multiple sclerosis; PD, Parkinson’s disease.
Table
Table 3. Sex-related differences in matrix metalloproteinases (MMP) in different cardiovascular diseases (CVDs).
Table 3. Sex-related differences in matrix metalloproteinases (MMP) in different cardiovascular diseases (CVDs).
MMPsCVDOrganismMaleFemaleReferences
MMP-2AneurismHuman/Mouse↑ in aorta [90,91]
Thoracic aortic aneurysmHuman ↑ in aorta[93,94]
Acute MIMouse↑ in affected heart [97]
Heart failureHuman ↓ in serum[119]
HypertensionHumanNo changeNo change[120]
Myocardial fibrosisHuman ↑ serum concentration associated with LOWER fibrosis[98]
MMP-3MIHuman ↓ in serum; positively correlated with inflammatory markers[99,100,101]
MMP-8Thoracic aortic aneurysmHuman ↓ in aorta[94]
Carotid atherosclerosisHumanNo differenceNo difference;
↓ in plaques. The difference disappeared in multivariate correction		[102,103]
MMP-9Aneurism/Ascending thoracic aortic aneurysmsHuman/Mouse↑ in the ascending aorta↑ in aorta[90,91,93,106]
MIMouse/Rat↑ in heart↓ in hearth[107,97]
post MIHuman/MouseNo change/Positively correlated with inflammatory markers; ↑ in HeartNo change[121,101]
Cardiac rupture following MIMouse↑ in left ventricle [108]
Myocardial fibrosisHuman ↑ serum concentration associated with HIGHER fibrosis[98]
CAD/CHDHuman↑ in serum↓ in serum[109,110,111,112]
Chest PainHuman ↑ in serum (patients with non-calcified and mixed plaques)[122]
HypertensionHumanNo changeNo change[120]
MMP-13Thoracic aortic aneurysmHuman/Rat ↓ in aorta[94,113]
MMP-14Thoracic aortic aneurysmHuman↑ in aorta [94]
CAD, coronary artery disease; CHD, coronary heart disease; MI, myocardial infarction; ↑ denotes an increase, ↓ a decrease.
Table
Table 4. Sex-related differences in matrix metalloproteinase (MMP) levels in different conditions of the central nervous system.
Table 4. Sex-related differences in matrix metalloproteinase (MMP) levels in different conditions of the central nervous system.
MMPsCNS ConditionsMaleFemaleReferences
MMP-1PD ↓ in serum[139]
MS and neurological controls ↑ CSF levels[140]
MMP-3AD, MCI, and cognitively normal individuals↑ frontal cortex protein levels [142]
↑ plasma levels↑ levels associated to greater cognitive decline[141]
Epilepsy↑ serum levels [143]
ICHassociated to long-term functional outcomes [145]
MMP-9Ischemic stroke↑ serum levels in acute phase [144]
MMP-10ICH Associated to long-term functional outcomes[145]
MS ↑ CSF levels[140]
CNS, central nervous system; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; ICH, intracerebral haemorrhage; MCI, mild cognitive impairment; MS, multiple sclerosis; PD, Parkinson’s disease; ↑ denotes an increase, ↓ a decrease.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Trentini, A.; Manfrinato, M.C.; Castellazzi, M.; Bellini, T. Sex-Related Differences of Matrix Metalloproteinases (MMPs): New Perspectives for These Biomarkers in Cardiovascular and Neurological Diseases. J. Pers. Med. 2022, 12, 1196. https://doi.org/10.3390/jpm12081196

AMA Style

Trentini A, Manfrinato MC, Castellazzi M, Bellini T. Sex-Related Differences of Matrix Metalloproteinases (MMPs): New Perspectives for These Biomarkers in Cardiovascular and Neurological Diseases. Journal of Personalized Medicine. 2022; 12(8):1196. https://doi.org/10.3390/jpm12081196

Chicago/Turabian Style

Trentini, Alessandro, Maria Cristina Manfrinato, Massimiliano Castellazzi, and Tiziana Bellini. 2022. "Sex-Related Differences of Matrix Metalloproteinases (MMPs): New Perspectives for These Biomarkers in Cardiovascular and Neurological Diseases" Journal of Personalized Medicine 12, no. 8: 1196. https://doi.org/10.3390/jpm12081196

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop