Next Article in Journal
Ellagic Acid and Cancer Hallmarks: Insights from Experimental Evidence
Next Article in Special Issue
Imipramine Treatment Alters Sphingomyelin, Cholesterol, and Glycerophospholipid Metabolism in Isolated Macrophage Lysosomes
Previous Article in Journal
Sexually Dimorphic Effects of Histamine Degradation by Enteric Glial Histamine N-Methyltransferase (HNMT) on Visceral Hypersensitivity
Previous Article in Special Issue
Dynamics of Docosahexaenoic Acid Utilization by Mouse Peritoneal Macrophages
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomolecules
Volume 13
Issue 11
10.3390/biom13111652
biomolecules-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

Intracranial Aneurysms and Lipid Metabolism Disorders: From Molecular Mechanisms to Clinical Implications

by
Tonglin Pan
1,2,
Yuan Shi
1,2,
Guo Yu
1,2,
Abdureshid Mamtimin
1,2 and
Wei Zhu
1,2,*
1
Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200090, China
2
Neurosurgical Institute, Fudan University, Shanghai 200032, China
*
Author to whom correspondence should be addressed.
Biomolecules 2023, 13(11), 1652; https://doi.org/10.3390/biom13111652
Submission received: 8 October 2023 / Revised: 23 October 2023 / Accepted: 1 November 2023 / Published: 14 November 2023
(This article belongs to the Collection Feature Papers in Biomacromolecules: Lipids)
Browse Figure
Review Reports Versions Notes

Abstract

:
Many vascular diseases are linked to lipid metabolism disorders, which cause lipid accumulation and peroxidation in the vascular wall. These processes lead to degenerative changes in the vessel, such as phenotypic transformation of smooth muscle cells and dysfunction and apoptosis of endothelial cells. In intracranial aneurysms, the coexistence of lipid plaques is often observed, indicating localized lipid metabolism disorders. These disorders may impair the function of the vascular wall or result from it. We summarize the literature on the relationship between lipid metabolism disorders and intracranial aneurysms below.

1. Introduction

Intracranial aneurysm (IA) is a localized dilatation or protrusion of the intracranial arterial wall, which is a common intracranial vascular lesion with a prevalence of approximately 3–6% [1]. IA has various clinical manifestations, ranging from asymptomatic to causing neurological dysfunction or compression of adjacent structures [2]. However, the most severe consequence is IA rupture leading to subarachnoid hemorrhage (SAH), which is a life-threatening acute cerebrovascular event with a mortality rate of up to 50% and a complication rate of up to 70% [3]. Therefore, preventing and treating IA formation and rupture is an important topic in intracranial vascular disease.
The pathological changes in intracranial aneurysms mainly include loss of the internal elastic layer, degradation of the extracellular matrix, and abnormal function of vascular smooth muscle cells. Currently, genetic factors, hemodynamic abnormalities, and various vascular risk factors are believed to participate in the formation process of IA. In the context of genetic susceptibility, the blood vessels at bifurcation sites are more prone to mechanical damage due to congenital structural weaknesses or local metabolic abnormalities under the impact of blood flow. The endothelial layer is the first to be compromised, followed by a series of changes within the vascular wall due to lipid deposition and the impact of blood flow. Inflammatory cells infiltrate and secrete inflammatory mediators, while smooth muscle cells undergo an inflammatory response, leading to phenotypic changes from a contractile to a secretory phenotype. With the alterations in the microstructure of the vessel wall, the influence of lipid deposition and the impact of blood flow further expand, intensifying the local inflammatory response. This results in apoptosis of endothelial cells and smooth muscle cells, ultimately weakening the mechanical strength within the vessel wall and causing localized outward bulging, forming an arterial aneurysm. As hemodynamics, inflammatory responses, and the local metabolic environment continue to change, the blood vessels gradually become weaker, promoting the development of the aneurysm, which eventually ruptures [3].
Lipid metabolism encompasses the biosynthesis and degradation of lipids, including fatty acids, triglycerides, and cholesterol. Specialized lipoproteins facilitate the transportation of lipids from the intestine to the liver (the primary site of lipid conversion) and between the liver and peripheral tissues. Lipid metabolism disorder (LMD) is a common condition characterized by abnormal blood levels of lipids or lipoproteins. LMD is a well-established risk factor for systemic atherosclerosis and cardiovascular diseases [4,5]. However, the role of LMD in IA formation and rupture is less clear [6,7,8]. It has been increasingly investigated in recent years. The formation and rupture of IA is a complex multifactorial process involving genetic, environmental, lifestyle, and other factors [9,10,11]. Among them, LMD could affect the progression of IA through several mechanisms, such as inducing systemic inflammation and oxidative stress, altering the lipid composition and metabolism of the intracranial artery wall, weakening the structural strength and elasticity of the intracranial artery wall, and modulating the expression and activity of various genes, proteins, and related signaling pathways [12]. As depicted in Figure 1, intracranial aneurysms are influenced by LMD at different stages of their development and rupture.
In addition to its potential role in IA formation, LMD could also be related to the severity and prognosis of SAH after IA rupture. LMD affects cerebral blood flow, cerebrovascular reactivity, cerebral autoregulation, and collateral circulation in patients with SAH [13]. This change could influence the occurrence and outcome of cerebral ischemia, vasospasm, delayed cerebral ischemia (DCI), and early brain injury (EBI) [14,15,16]. Moreover, LMD could modulate the inflammatory response, oxidative stress, blood-brain barrier disruption, neuronal injury, and neurogenesis after SAH, which can affect the recovery and regeneration of brain tissue [17].
Therefore, exploring the relationship between LMD and IA and its potential role in biomarker search and treatment is of great significance for understanding the pathogenesis and development of IA, improving early diagnoses and intervention, and reducing the incidence and mortality of SAH. In this article, we aim to discuss recent advances in the correlation between LMD and IA and to propose future research directions. The main contents of this article include (1) reviewing the altered lipid environment associated with vascular diseases; (2) analyzing the relationship between LMD and IA formation; (3) analyzing the relationship between LMD and IA rupture; (4) analyzing the relationship between LMD and SAH after IA rupture; and (5) discussing the possibility of LMD as a biomarker and therapeutic target for IA.

2. Dysregulated Lipid Metabolism in Vascular Diseases

2.1. Fatty Acyls

Fatty acyls are chain-like carboxylic acids composed of carbon, hydrogen, and oxygen and are the basic units of lipid metabolism. Depending on the chain length and degree of unsaturation, fatty acyls can be classified into short-, medium-, long-, and extralong-chain types, as well as saturated, monounsaturated, and polyunsaturated types [18]. The effects of fatty acyls on vascular endothelial cells (VECs) and vascular diseases mainly depend on their structural characteristics and metabolic pathways. In general, saturated fatty acyls such as palmitic acid and stearic acid adversely affect VECs, while unsaturated fatty acyls such as oleic acid, linoleic acid, arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have protective effects on VECs [19,20,21].
Saturated fatty acyls induce various abnormal phenomena in VECs, such as oxidative stress, inflammatory response, endoplasmic reticulum (ER) stress, apoptosis, and autophagy, thereby impairing VEC barrier function, increasing permeability, promoting leukocyte adhesion and migration, and leading to atherosclerosis formation [22,23,24]. These mechanisms include activating Toll-like receptor 2/4 (TLR2/4), nuclear factor-kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and protein kinase C (PKC), as well as inducing NLR family pyrin domain containing 3 (NLRP3) inflammasome assembly and activation [25,26,27,28]. In addition, saturated fatty acyls can also alter VEC biological characteristics by affecting membrane fluidity, protein palmitoylation, mitochondrial function, and other aspects [29].
Unsaturated fatty acyls have the opposite effects. They protect VECs from oxidative stress, the inflammatory response, ER stress, apoptosis, and autophagy damage, thereby maintaining VEC barrier function, reducing permeability, inhibiting leukocyte adhesion and migration, and preventing atherosclerosis development. These mechanisms include activating peroxisome proliferator-activated receptor alpha/gamma (PPARα/γ), AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and other signaling pathways, as well as inhibiting NLRP3 inflammasome assembly and activation [30,31,32]. In addition, unsaturated fatty acyls could also improve VEC biological characteristics by affecting membrane fluidity, protein phosphorylation, mitochondrial function, and other aspects [33,34,35].

2.2. Triglycerides

Triglycerides are the predominant form of lipid storage in the body and are transported by lipoproteins in the plasma. Elevated triglyceride levels are associated with an increased risk of cardiovascular disease, especially in the presence of low high-density lipoprotein (HDL) cholesterol levels [36]. The mechanisms by which triglycerides and their associated lipoproteins contribute to atherosclerosis and thrombosis are not fully elucidated but could involve direct infiltration of the arterial wall, inflammation, oxidative stress, endothelial dysfunction, and impaired fibrinolysis [37]. Several genetic and environmental factors influence triglyceride levels, such as diet, alcohol intake, obesity, diabetes, insulin resistance, and medications [38]. Lifestyle modification and pharmacological therapy can lower triglyceride levels and potentially reduce cardiovascular risk [39]. However, the evidence for the benefit of triglyceride lowering on clinical outcomes is limited and inconsistent [40].

2.3. Glycerophospholipids and Sphingolipids

Glycerophospholipids, primarily residing in the cellular membrane, act as structural components, providing integrity and fluidity. They function as precursors for bioactive lipids such as diacylglycerols and phosphatidic acid, which participate in cellular signaling [41]. Importantly, certain glycerophospholipid species have been implicated in cerebrovascular disease, including stroke [42]. The generation of platelet-activating factor (a type of alkylacylglycerophosphocholine) in endothelial cells could contribute to the inflammatory response after ischemic stroke. This highlights the relevance of glycerophospholipid metabolism in stroke pathology [43]. On the other hand, sphingolipids, complex molecules derived from the aliphatic amino alcohol sphingosine, play key roles in cell signaling and recognition, endocytosis, and intracellular trafficking [5]. Ceramides, a group of sphingolipids, are considered bioactive lipids involved in the regulation of cellular processes such as inflammation, oxidative stress, and apoptosis. Elevated ceramide levels have been observed in brain tissue after stroke, which is postulated to contribute to neuronal cell death [44]. Moreover, the roles of sphingosine-1-phosphate (S1P) and its receptors in regulating blood-brain barrier integrity, neuroinflammation, and neuronal survival suggest the relevance of sphingolipid signaling in neurovascular diseases [45].

2.4. Apolipoprotein

LpA is a unique lipoprotein that consists of a low-density lipoprotein (LDL)-like particle and a glycoprotein called apolipoprotein A (ApoA). ApoA is synthesized in the liver and covalently linked to apolipoprotein B-100 (ApoB-100), the main protein component of LDL, with a disulfide bond. ApoA has a high structural similarity to plasminogen, the precursor of plasmin, which is an enzyme that dissolves blood clots. ApoA contains several repeating units called kringle domains, which are also found in plasminogen. The number and size of these kringle domains vary among individuals, resulting in different isoforms of ApoA and LpA.
Within the ApoA molecule, ten kringle IV subtypes could be identified. The heterogeneity in ApoA isoform sizes primarily arises from varying copy numbers of kringle IV type 2, ranging from a couple to over forty [46,47,48]. This intricate kringle IV type 2 repeat system creates a broad molecular weight diversity of LpA. The assembly of LpA remains an enigma, involving a series of intricate noncovalent interactions followed by the formation of a crucial disulfide bond [49,50]. Nevertheless, an inverse correlation is observed between plasma LpA levels and ApoA isoform size, primarily attributed to the constant production of ApoA in the liver, with smaller isoforms being generated more prolifically than larger ones [51]. Despite extensive research, the clearance pathways for LpA remain largely elusive, although LDLR-, VLDLR-, CD36-, and SR-B1-mediated hepatic clearance and proteolytic cleavage may play a role [52].
Through several mechanisms, LpA is suspected to be causatively linked with atherosclerotic cardiovascular disease (ASCVD). LDL-like particles bearing ApoA could instigate atherosclerosis, while the inherent properties of ApoA potentially exacerbate atherogenic risks. The binding sites of ApoA facilitate adherence to the damaged endothelium and subsequent particle entrapment in the subintimal space [53]. Additionally, oxidized phospholipids on ApoA could instigate plaque inflammation and atherosclerosis, with the propensity to promote endothelial dysfunction and drive inflammatory cascades [54].
An elevated LpA level has also been implicated in aortic valve calcification and is thus recognized as a risk factor for calcific aortic stenosis. These findings underscore the potential of LpA as a biomarker, since heightened plasma LpA levels are independently linked with increased ASCVD risk and calcific aortic stenosis. The largely genetically determined plasma LpA levels are influenced by the size of the LPA gene, a surrogate for the kringle IV type 2 copy number, and specific single-nucleotide polymorphisms [55]. Exploiting the presumed causative association between LpA and ASCVD, therapeutics such as pelacarsen, an antisense oligonucleotide targeting ApoA, are currently under development. As such, a deeper understanding of apolipoprotein biology will likely pave the way for future therapeutic strategies aimed at mitigating ASCVD risk [56].

3. Lipid Metabolism and IA Formation

Intracranial aneurysm formation is associated with genetic susceptibility. Emerging research has illuminated the potential connection between dysregulated lipid metabolism and the genetic susceptibility of IA. Recent Mendelian randomization studies provide compelling genetic evidence that underscores the intimate relationship between lipid levels and the development of IA. In a seminal study, Mendelian randomization was employed to explore the associations of modifiable lifestyle factors and cardiometabolic factors with the risk of intracranial IA. Notably, genetically predicted decreased physical activity, higher triglyceride levels, higher body mass index, and lower levels of low-density lipoprotein cholesterol appeared to be associated with a higher risk of IA and aneurysmal subarachnoid hemorrhage [57]. Subsequently, a study further revealed the effects of blood lipids and lipid-modifying drugs on IA via Mendelian randomization. They demonstrated that genetically determined HDL-C and LDL-C levels were associated with a reduced risk of IA and ruptured IA [58]. These findings accentuate the pivotal role of lipid metabolism in the pathogenesis of IA.
In particular, several key proteins and genetic variations, such as apolipoprotein (APO) and related mutations, have been implicated in the genetic susceptibility of aneurysms. Apolipoprotein E (APOE), a critical regulator of lipid metabolism, has been associated with the formation of IAs in some investigations. For instance, the study by Liu et al. revealed a significantly higher frequency of the APOE E2/E2 and APOE E2/E3 genotypes in IA patients than in healthy controls [59]. Such findings suggested that certain variations in the APOE gene could augment the risk of IA formation. Likewise, LpA has also been examined as a potential risk factor for IAs [60], and the results indicated that the average LpA levels were over twice as high in familial members with IAs compared to the control group, implying that elevated LpA levels may be implicated in IA formation [61,62,63].
Moreover, a study revealed alterations in the expression of several genes, such as ABCA1, APOA1, and LDLR, associated with lipid metabolism in patients with IA. Notably, an increase in the expression of the LDLR gene in IA patients underscores the potential role of lipid metabolism in the pathogenesis of IA. Furthermore, a specific genotype (A/G) and allele (A) of the APOA1 gene were associated with an increased incidence of IA, whereas another genotype (G/G) and allele (G) indicated an opposite tendency. These findings substantiate the notion that genetic variations may significantly influence the development of IA [64]. Second, a study further emphasized the distinct impacts of lipid-metabolism-related genetic variations in intracranial and abdominal aortic aneurysms. The research demonstrated that genetic risk profiles associated with serum lipid levels and coronary artery disease (CAD) correlate with the risk of abdominal aortic aneurysms but not IAs. Conversely, the genetic risk profile associated with blood pressure correlates with the risk of IAs but not abdominal aortic aneurysms [65]. These observations suggest that a lipid-metabolism-associated gene could influence the formation and development of different types of aneurysms via diverse mechanisms.

4. Lipid Metabolism and IA Rupture

The role of lipid metabolism has come under scrutiny in the study of several factors contributing to IA rupture. Abnormalities in lipid metabolism could cause inflammation, oxidative stress, and regressive changes in the blood vessel walls, all seen as significant risk factors for IA rupture. First, arachidonic acid (AA) is a polyunsaturated fatty acid that can transform into a range of inflammatory agents. However, a study identified that AA metabolism in the unruptured IA wall remains comparatively stable, possibly due to the relatively diminished oxidative stress and inflammation [66]. Next, the build-up of lipids plays a significant role in IA rupture. The foamy transformation of smooth muscle cells (SMCs) signifies lipid accumulation, as they take in and store an excess amount of lipids. Additionally, the anomalous expression of lipid-transporting proteins such as lipoproteins and ABCA1 in the wall of IA could influence the accumulation and clearance of lipids [67]. Accumulation of lipids and oxidized lipids, together with a drop in the plasma levels of antioxidative lipid antibodies and antiatherogenic proteins, could be linked to the regressive changes and rupture of the IA wall [8,68,69]. Regarding lipid factors, research has discovered that the concentration of LpA in the IA sac is correlated with an increase in the IA wall enhancement and could be connected to the regressive changes and rupture of IA [70]. Additionally, a high-fat diet could stimulate the advancement of IA by increasing serum cholesterol levels [71]. Finally, studies found that sex hormones such as testosterone could enhance the risk of brain vessel damage and IA rupture by impacting lipid metabolism, for instance, by lowering the levels of HDL in plasma [72]. These research outcomes not only fortify our comprehension of the mechanisms of IA rupture but also offer new potential approaches for preventing and treating IA, such as lessening IA by improving lipid metabolism.

5. Lipid Metabolism and aSAH

Following aneurysm rupture, there is a significant alteration in cerebrospinal fluid lipid metabolism, including an overproduction of bioactive lipid molecules such as inflammatory mediators and oxidative stress factors. These elements could further instigate cellular injury and vascular responses, amplifying brain damage. For instance, alterations in the metabolism of arachidonic acid could enhance the production of inflammatory mediators such as prostaglandins and leukotrienes [73,74,75,76,77,78,79,80]. Furthermore, lipid peroxidation and cerebral vasospasm showed a close relationship. Lipid peroxidation could induce cell membrane injury, which in turn triggers the contraction of vascular SMCs, leading to cerebral vasospasm. Lipid peroxidation products could also exacerbate cerebral vasospasm by impairing endothelial cell function, affecting vasodilation [81,82,83,84]. Last, the genotype of APOE could influence lipid metabolism following aneurysm rupture and the resultant patient recovery and outcomes. While certain studies have identified an association between the APOE ε4 allele and poor prognosis post-SAH, others have not found such a correlation [85,86,87,88,89]. This suggests that the influence and recovery following cerebral aneurysm rupture linked to the APOE ε4 allele may be complex and potentially affected by multiple factors. In summary, changes in lipid metabolism post aneurysm rupture, the relationship between lipid peroxidation and cerebral vasospasm, and the role of APOE all bear significant importance for understanding the biological mechanisms and prognosis of SAH. However, these areas necessitate further research and exploration.

6. Lipid Metabolism as a Biomarker and Therapeutic Target for IA

6.1. Lipid Metabolites as Biomarkers for IA

Aneurysmal subarachnoid hemorrhage (aSAH) is one of the major diseases that causes death and disability. Therefore, it is necessary to find biomarkers that can evaluate the therapeutic effect and prognosis, stratify aSAH patients, and objectively monitor the response to treatment.
Emerging research illuminates the integral role of lipid metabolism as a biomarker in predicting the onset and evolution of IA and prognosticating aneurysmal (aSAH) outcomes. Initially, lipid metabolism was implicated in the growth and development of IA. Markers such as F2-isoprostanes and F4-neuroprostanes, indicators of oxidative stress, have been underscored as being instrumental in the progression of IA [90,91,92]. Concurrently, compelling evidence links total cholesterol (TC) and HDL levels as independent prognostic indicators of mortality and delayed cerebral ischemia in the aftermath of aSAH [93]. Finally, the concentration of cysteinyl-leukotrienes (cys-LT) in cerebrospinal fluid (CSF) following aSAH has been found to correlate significantly with cerebral vasospasm [94]. This underscores the potential role of cys-LT, another product of arachidonic acid metabolism, in the etiology of vasospasm. In conclusion, lipid metabolism serves as a pivotal biomarker in IA and aSAH. It offers valuable insights into disease pathophysiology, informs predictive modelling of disease progression, and could potentially enhance patient outcome prognostication.

6.2. Lipid Metabolism Disorder as a Therapeutic Target for IA

The treatment of IA mainly relies on surgical or endovascular approaches, such as clipping or coiling, but these methods have certain risks and limitations and cannot prevent the recurrence or de novo formation of aneurysms. Therefore, finding effective pharmacological interventions to prevent or delay the formation, growth, and rupture of aneurysms is an important topic in the field of IA. Lipid metabolism disorder as a target in the treatment of IA and SAH has received much attention from many studies.
The therapeutic potential of statins has been validated across several domains, including but not limited to their capacity to mitigate the onset and progression of aneurysms. Numerous animal-based investigations have elucidated their efficacy. For instance, simvastatin has an inhibitory effect on the inflammatory response within the aneurysm wall of a rat cerebral artery aneurysm model [95]. Concurrently elevating the prevalence of endothelial cells and SMCs, as well as downregulating the expression and activity of metalloproteinase-2 and metalloproteinase-9, forestalls damage to and remodeling of the aneurysm wall. Similarly, rosuvastatin can enhance endothelialization at the aneurysm neck in a rat embolization model [96,97], augment the number of endothelial progenitor cells (EPCs), and restrict inflammation of the vascular wall. These findings suggested that statins could confer protection to or facilitate the repair of the aneurysm wall via a multitude of mechanisms, forestalling its expansion and rupture. Moreover, in the context of clinical trials, a wealth of studies point towards the ability of statins to enhance the prognosis of SAH patients. For instance, a study demonstrated that oral pravastatin (40 mg/d) significantly reduced the occurrence of cerebral vasospasm and ischemic neurological deficits [98]. Similarly, in a study of 592 SAH patients treated with clipping or coiling surgery, atorvastatin (20 mg/d) significantly diminished the incidence of cerebral vasospasm and cerebral infarction and enhanced the Glasgow outcome score at the 6-month mark [99]. Furthermore, in a study of 1214 SAH patients drawn from 10 randomized controlled trials who received varying types and doses of statins, there was a significant reduction in the incidence of cerebral vasospasm, ischemic neurological deficits, and cerebral infarction. However, no significant impact on the mortality rate or neurological function prognosis was detected [100]. These findings suggested that statins could enhance vascular endothelial function, resist oxidative stress, and inhibit vascular inflammation and coagulation, thus mitigating cerebral vasospasm and ischemic injury post-SAH. Statins, as a class of effective drugs to improve lipid metabolism, have shown some effects in animal experiments and clinical trials, but further research is needed to explore their optimal dose timing and indications as well as their possible adverse reactions and complications. As presented in Table 1, the enrolled clinical trials and subjects varied in terms of their basic characteristics, such as the study design, sample size, intervention, and outcome measures.
Eicosapentaenoic acid (EPA), an ω-3 fatty acid, has been identified to demonstrate considerable potential in the management of IA and SAH following aneurysm rupture. Its principal effects appear to reside in the inhibition of cerebral vasospasm (CV) and inflammatory responses. A study demonstrated that EPA significantly reduces the incidence of cerebral vasospasm and cerebrovascular infarction induced with CV in SAH patients [111,112]. A further study elucidated that the combined application of EPA and DHA, another ω-3 fatty acid, could markedly attenuate vasospasm, reduce the occurrence of new-onset cerebrovascular infarction due to spasm, and improve the clinical prognosis at 90 days post-SAH [113]. A study specifically investigated the impact of EPA on the progression of IA. Their findings suggested that EPA could significantly inhibit the size of IA in rats and degenerative changes in the media of arterial walls. Furthermore, EPA also appears to suppress inflammatory responses within the lesion, including macrophage infiltration and the expression of MCP-1, a chemokine primarily responsible for attracting macrophage accumulation in lesion areas [114]. However, these findings are largely based on small-scale or animal studies, and further large-scale, randomized controlled trials are required to validate the effectiveness and safety of EPA in humans.

7. Conclusions

Several studies have proposed possible biological mechanisms by which lipid metabolism disorders affect the development and rupture of intracranial aneurysms by selecting typical biomarkers. However, these studies did not systematically explore the molecular alterations caused by lipid metabolism disorders in intracranial aneurysms. In recent years, omics techniques have become effective tools for the discovery of novel biomarkers and biological pathways. However, there are no studies that have implemented proteomics, lipidomics, or combined multiple omics techniques to comprehensively detect systemic molecular changes caused by lipid metabolism disorders in intracranial aneurysms and to explore the complex connections between these molecules. Future studies should focus more on this direction to elucidate the critical role of lipid metabolism disorders in the development and rupture of intracranial aneurysms.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82171311 to W.Z., No. 82271339 to P.L.), Shanghai Excellent Academic Leader Program (No. 21XD1400600 to W.Z.), Clinical Research Plan of SHDC (No. SHDC2020CR2034B to W.Z., No. SHDC2020CR4033 to K.Q.), Shanghai Science and Technology Commission Project (No. 23ZR1408700 to K.Q.), Shanghai Sailing Program (23Y1404500 to Y.S.), Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01) and Zhang Jiang Laboratory, and CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-008).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Liu, J.; Zou, X.; Zhao, Y.; Jin, Z.; Tu, J.; Ning, X.; Li, J.; Yang, X.; Wang, J. Prevalence and Risk Factors for Unruptured Intracranial Aneurysms in the Population at High Risk for Aneurysm in the Rural Areas of Tianjin. Front. Neurol. 2022, 13, 853054. [Google Scholar] [CrossRef] [PubMed]
  2. Li, W.; Ye, M.; Cimpoca, A.; Henkes, H.; Wang, H.; Xu, X.; Gu, Y.; Shi, H.; Ji, H.; Wang, F.; et al. Avenir® vs. AxiumTM Coils for the Treatment of Intracranial Aneurysms: Results of a Multicenter Randomized Controlled Trial With Short-Term Follow-Up. Front. Neurol. 2021, 12, 817989. [Google Scholar] [CrossRef]
  3. Jin, J.; Duan, J.; Du, L.; Xing, W.; Peng, X.; Zhao, Q. Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies. Front. Immunol. 2022, 13, 1027756. [Google Scholar] [CrossRef]
  4. Cheon, S.Y.; Cho, K. Lipid metabolism, inflammation, and foam cell formation in health and metabolic disorders: Targeting mTORC1. J. Mol. Med. 2021, 99, 1497–1509. [Google Scholar] [CrossRef] [PubMed]
  5. Wang, W.; Zhu, N.; Yan, T.; Shi, Y.-N.; Chen, J.; Zhang, C.-J.; Xie, X.-J.; Liao, D.-F.; Qin, L. The crosstalk: Exosomes and lipid metabolism. Cell Commun. Signal 2020, 18, 119. [Google Scholar] [CrossRef] [PubMed]
  6. Løvik, K.; Laupsa-Borge, J.; Logallo, N.; Helland, C.A. Dyslipidemia and rupture risk of intracranial aneurysms—A systematic review. Neurosurg. Rev. 2021, 44, 3143–3150. [Google Scholar] [CrossRef]
  7. Ou, C.; Qian, Y.; Zhang, X.; Liu, J.; Liu, W.; Su, H.; Zhang, N.; Zhang, J.; He, X.; Duan, C.-Z. Elevated Lipid Infiltration Is Associated With Cerebral Aneurysm Rupture. Front. Neurol. 2020, 11, 154. [Google Scholar] [CrossRef]
  8. Frösen, J.; Tulamo, R.; Heikura, T.; Sammalkorpi, S.; Niemelä, M.; Hernesniemi, J.; Levonen, A.-L.; Hörkkö, S.; Ylä-Herttuala, S. Lipid accumulation, lipid oxidation, and low plasma levels of acquired antibodies against oxidized lipids associate with degeneration and rupture of the intracranial aneurysm wall. Acta Neuropathol. Commun. 2013, 1, 71. [Google Scholar] [CrossRef]
  9. van der Kamp, L.T.; Rinkel, G.J.E.; Verbaan, D.; van den Berg, R.; Vandertop, W.P.; Murayama, Y.; Ishibashi, T.; Lindgren, A.; Koivisto, T.; Teo, M.; et al. Risk of Rupture After Intracranial Aneurysm Growth. JAMA Neurol. 2021, 78, 1228–1235. [Google Scholar] [CrossRef]
  10. Renowden, S.; Nelson, R. Management of incidental unruptured intracranial aneurysms. Prac. Neurol. 2020, 20, 347–355. [Google Scholar] [CrossRef]
  11. Krischek, B.; Tatagiba, M. The influence of genetics on intracranial aneurysm formation and rupture: Current knowledge and its possible impact on future treatment. Adv. Tech. Stand. Neurosurg. 2008, 33, 131–147. [Google Scholar]
  12. Vanrossomme, A.E.; Eker, O.F.; Thiran, J.P.; Courbebaisse, G.P.; Zouaoui Boudjeltia, K. Intracranial Aneurysms: Wall Motion Analysis for Prediction of Rupture. AJNR. Am. J. Neuroradiol. 2015, 36, 1796–1802. [Google Scholar] [CrossRef]
  13. Tang, H.; Wang, Q.; Xu, F.; Zhang, X.; Zeng, Z.; Yan, Y.; Lu, Z.; Xue, G.; Zuo, Q.; Luo, Y.; et al. Underlying mechanism of hemodynamics and intracranial aneurysm. Chin. Neurosurg. J. 2021, 7, 44. [Google Scholar] [CrossRef]
  14. Budohoski, K.P.; Guilfoyle, M.; Helmy, A.; Huuskonen, T.; Czosnyka, M.; Kirollos, R.; Menon, D.K.; Pickard, J.D.; Kirkpatrick, P.J. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J. Neurol. Neurosurg. Psychiatry 2014, 85, 1343–1353. [Google Scholar] [CrossRef]
  15. Yu, W. Vasospasm and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: Recent Advances and Future Directions in Translational Research. Transl. Stroke Res. 2023, 14, 119–120. [Google Scholar] [CrossRef] [PubMed]
  16. Koenig, M.A. Management of delayed cerebral ischemia after subarachnoid hemorrhage. CONTINUUM Lifelong Learn. Neurol. 2012, 18, 579–597. [Google Scholar] [CrossRef] [PubMed]
  17. Wu, L.; Xiong, X.; Wu, X.; Ye, Y.; Jian, Z.; Zhi, Z.; Gu, L. Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury. Front. Mol. Neurosci. 2020, 13, 28. [Google Scholar] [CrossRef] [PubMed]
  18. Yamagata, K. Fatty acids act on vascular endothelial cells and influence the development of cardiovascular disease. Prostaglandins Other Lipid Mediat 2023, 165, 106704. [Google Scholar] [CrossRef]
  19. Vafeiadou, K.; Weech, M.; Sharma, V.; Yaqoob, P.; Todd, S.; Williams, C.M.; Jackson, K.G.; Lovegrove, J.A. A review of the evidence for the effects of total dietary fat, saturated, monounsaturated and n-6 polyunsaturated fatty acids on vascular function, endothelial progenitor cells and microparticles. Br. J. Nutr. 2012, 107, 303–324. [Google Scholar] [CrossRef]
  20. Du, Y.; Taylor, C.G.; Zahradka, P. Modulation of endothelial cell responses and vascular function by dietary fatty acids. Nutr. Rev. 2019, 77, 614–629. [Google Scholar] [CrossRef]
  21. Jackson, K.G.; Newens, K.J.; Fry, M.J.; Thompson, A.K.; Williams, C.M. Differential effects of single fatty acids and fatty acid mixtures on the phosphoinositide 3-kinase/Akt/eNOS pathway in endothelial cells. Eur. J. Nutr. 2022, 61, 2463–2473. [Google Scholar] [CrossRef] [PubMed]
  22. Li, X.; Gonzalez, O.; Shen, X.; Barnhart, S.; Kramer, F.; Kanter, J.E.; Vivekanandan-Giri, A.; Tsuchiya, K.; Handa, P.; Pennathur, S.; et al. Endothelial acyl-CoA synthetase 1 is not required for inflammatory and apoptotic effects of a saturated fatty acid-rich environment. Arter. Thromb. Vasc. Biol. 2013, 33, 232–240. [Google Scholar] [CrossRef] [PubMed]
  23. Mantzaris, M.D.; Tsianos, E.V.; Galaris, D. Interruption of triacylglycerol synthesis in the endoplasmic reticulum is the initiating event for saturated fatty acid-induced lipotoxicity in liver cells. FEBS J. 2011, 278, 519–530. [Google Scholar] [CrossRef]
  24. Anderson, E.K.; Hill, A.A.; Hasty, A.H. Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis. Arter. Thromb. Vasc. Biol. 2012, 32, 1687–1695. [Google Scholar] [CrossRef] [PubMed]
  25. Hwang, D.H.; Kim, J.-A.; Lee, J.Y. Mechanisms for the activation of Toll-like receptor 2/4 by saturated fatty acids and inhibition by docosahexaenoic acid. Eur. J. Pharmacol. 2016, 785, 24–35. [Google Scholar] [CrossRef] [PubMed]
  26. Lee, J.Y.; Sohn, K.H.; Rhee, S.H.; Hwang, D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J. Biol. Chem. 2001, 276, 16683–16689. [Google Scholar] [CrossRef]
  27. Dallak, M.A. Acylated ghrelin induces but deacylated ghrelin prevents hepatic steatosis and insulin resistance in lean rats: Effects on DAG/ PKC/JNK pathway. Biomed. Pharmacother. 2018, 105, 299–311. [Google Scholar] [CrossRef]
  28. Gupta, P.; Sharma, G.; Lahiri, A.; Barthwal, M.K. FOXO3a acetylation regulates PINK1, mitophagy, inflammasome activation in murine palmitate-conditioned and diabetic macrophages. J. Leukoc. Biol. 2022, 111, 611–627. [Google Scholar] [CrossRef]
  29. Sardar, A.; Dewangan, N.; Panda, B.; Bhowmick, D.; Tarafdar, P.K. Lipid and Lipidation in Membrane Fusion. J. Membr. Biol. 2022, 255, 691–703. [Google Scholar] [CrossRef] [PubMed]
  30. Ghosh, A.; Gao, L.; Thakur, A.; Siu, P.M.; Lai, C.W.K. Role of free fatty acids in endothelial dysfunction. J. Biomed. Sci. 2017, 24, 50. [Google Scholar] [CrossRef]
  31. Mazzocchi, A.; De Cosmi, V.; Risé, P.; Milani, G.P.; Turolo, S.; Syrén, M.-L.; Sala, A.; Agostoni, C. Bioactive Compounds in Edible Oils and Their Role in Oxidative Stress and Inflammation. Front. Physiol. 2021, 12, 659551. [Google Scholar] [CrossRef]
  32. Chipurupalli, S.; Samavedam, U.; Robinson, N. Crosstalk Between ER Stress, Autophagy and Inflammation. Front. Med. 2021, 8, 758311. [Google Scholar] [CrossRef]
  33. Hart, C.M.; Tolson, J.K.; Block, E.R. Fatty acid supplementation protects pulmonary artery endothelial cells from oxidant injury. Am. J. Respir. Cell Mol. Biol. 1990, 3, 479–489. [Google Scholar] [CrossRef] [PubMed]
  34. Sekharam, K.M.; Patel, J.M.; Block, E.R. Effect of polyunsaturated fatty acids and phospholipids on [3H]-vitamin E incorporation into pulmonary artery endothelial cell membranes. J. Cell. Physiol. 1990, 145, 555–563. [Google Scholar] [CrossRef] [PubMed]
  35. Block, E.R.; Patel, J.M.; Sheridan, N.P. Endotoxin protects against hyperoxic decrease in membrane fluidity in endothelial cells but not in fibroblasts. Lab. Invest. 1986, 54, 146–153. [Google Scholar] [PubMed]
  36. Duran, E.K.; Aday, A.W.; Cook, N.R.; Buring, J.E.; Ridker, P.M.; Pradhan, A.D. Triglyceride-Rich Lipoprotein Cholesterol, Small Dense LDL Cholesterol, and Incident Cardiovascular Disease. J. Am. Coll. Cardiol. 2020, 75, 2122–2135. [Google Scholar] [CrossRef] [PubMed]
  37. Esan, O.; Wierzbicki, A.S. Triglycerides and cardiovascular disease. Curr. Opin. Cardiol. 2021, 36, 469–477. [Google Scholar] [CrossRef]
  38. Carrasquilla, G.D.; Christiansen, M.R.; Kilpeläinen, T.O. The Genetic Basis of Hypertriglyceridemia. Curr. Atheroscler. Rep. 2021, 23, 39. [Google Scholar] [CrossRef]
  39. Hussain, A.; Ballantyne, C.M.; Saeed, A.; Virani, S.S. Triglycerides and ASCVD Risk Reduction: Recent Insights and Future Directions. Curr. Atheroscler. Rep. 2020, 22, 25. [Google Scholar] [CrossRef] [PubMed]
  40. Sillars, A.; Sattar, N. Management of Lipid Abnormalities in Patients with Diabetes. Curr. Cardiol. Rep. 2019, 21, 147. [Google Scholar] [CrossRef]
  41. Iqbal, J.; Walsh, M.T.; Hammad, S.M.; Hussain, M.M. Sphingolipids and Lipoproteins in Health and Metabolic Disorders. Trends Endocrinol. Metab. 2017, 28, 506–518. [Google Scholar] [CrossRef]
  42. Jiang, W.; Chen, J.; Gong, L.; Liu, F.; Zhao, H.; Mu, J. Alteration of Glycerophospholipid Metabolism in Hippocampus of Post-stroke Depression Rats. Neurochem. Res. 2022, 47, 2052–2063. [Google Scholar] [CrossRef] [PubMed]
  43. Shaik, N.F.; Regan, R.F.; Naik, U.P. Platelets as drivers of ischemia/reperfusion injury after stroke. Blood Adv. 2021, 5, 1576–1584. [Google Scholar] [CrossRef] [PubMed]
  44. Mao, R.; Zong, N.; Hu, Y.; Chen, Y.; Xu, Y. Neuronal Death Mechanisms and Therapeutic Strategy in Ischemic Stroke. Neurosci. Bull. 2022, 38, 1229–1247. [Google Scholar] [CrossRef]
  45. Magaye, R.R.; Savira, F.; Hua, Y.; Kelly, D.J.; Reid, C.; Flynn, B.; Liew, D.; Wang, B.H. The role of dihydrosphingolipids in disease. Cell Mol. Life Sci. 2019, 76, 1107–1134. [Google Scholar] [CrossRef] [PubMed]
  46. Ward, N.C.; Nolde, J.M.; Chan, J.; Carnagarin, R.; Watts, G.F.; Schlaich, M.P. Lipoprotein (a) and Hypertension. Curr. Hypertens Rep. 2021, 23, 44. [Google Scholar] [CrossRef] [PubMed]
  47. Rhainds, D.; Brodeur, M.R.; Tardif, J.-C. Lipoprotein (a): When to Measure and How to Treat? Curr. Atheroscler Rep. 2021, 23, 51. [Google Scholar] [CrossRef]
  48. Saeed, A.; Kinoush, S.; Virani, S.S. Lipoprotein (a): Recent Updates on a Unique Lipoprotein. Curr. Atheroscler Rep. 2021, 23, 41. [Google Scholar] [CrossRef]
  49. Coassin, S.; Kronenberg, F. Lipoprotein(a) beyond the kringle IV repeat polymorphism: The complexity of genetic variation in the LPA gene. Atherosclerosis 2022, 349, 17–35. [Google Scholar] [CrossRef]
  50. Grüneis, R.; Weissensteiner, H.; Lamina, C.; Schönherr, S.; Forer, L.; Di Maio, S.; Streiter, G.; Peters, A.; Gieger, C.; Kronenberg, F.; et al. The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat. J. Lipid Res. 2022, 63, 100306. [Google Scholar] [CrossRef]
  51. Tomova, V.D.; Alexandrova, M.L.; Atanasova, M.A.; Tzekova, M.L.; Rashev, T.R.; Ahmad, S. Plasma lipoprotein(a) concentration as an independent predictor of hemodynamic progression of aortic valve stenosis. Mol. Cell. Biochem. 2020, 472, 199–207. [Google Scholar] [CrossRef] [PubMed]
  52. Brown, P.M.; Kennedy, D.J.; Morton, R.E.; Febbraio, M. CD36/SR-B2-TLR2 Dependent Pathways Enhance Porphyromonas gingivalis Mediated Atherosclerosis in the Ldlr KO Mouse Model. PLoS ONE 2015, 10, e0125126. [Google Scholar] [CrossRef] [PubMed]
  53. Bhatia, H.S.; Wilkinson, M.J. Lipoprotein(a): Evidence for Role as a Causal Risk Factor in Cardiovascular Disease and Emerging Therapies. J. Clin. Med. 2022, 11, 6040. [Google Scholar] [CrossRef] [PubMed]
  54. Lim, G.B. Inflammatory and atherogenic effects of oxidized phospholipids. Nat. Rev. Cardiol. 2018, 15, 441. [Google Scholar] [CrossRef] [PubMed]
  55. de Oliveira Sá, M.P.B.; Cavalcanti, L.R.P.; Perazzo, Á.M.; Gomes, R.A.F.; Clavel, M.-A.; Pibarot, P.; Biondi-Zoccai, G.; Zhigalov, K.; Weymann, A.; Ruhparwar, A.; et al. Calcific Aortic Valve Stenosis and Atherosclerotic Calcification. Curr. Atheroscler Rep. 2020, 22, 2. [Google Scholar] [CrossRef] [PubMed]
  56. Mehta, A.; Vasquez, N.; Ayers, C.R.; Patel, J.; Hooda, A.; Khera, A.; Blumenthal, R.S.; Shapiro, M.D.; Rodriguez, C.J.; Tsai, M.Y.; et al. Independent Association of Lipoprotein(a) and Coronary Artery Calcification With Atherosclerotic Cardiovascular Risk. J. Am. Coll. Cardiol. 2022, 79, 757–768. [Google Scholar] [CrossRef]
  57. Zhang, B.; Dong, S.; Miao, Y.; Song, G.; Yuan, F.; Liu, L.; Xia, S.; Qin, Y.; Huo, X.; Wu, Z.; et al. Effects of blood lipids and lipid-modifying drugs on intracranial aneurysms. Eur. J. Neurol. 2022, 29, 2967–2975. [Google Scholar] [CrossRef]
  58. Karhunen, V.; Bakker, M.K.; Ruigrok, Y.M.; Gill, D.; Larsson, S.C. Modifiable Risk Factors for Intracranial Aneurysm and Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study. J. Am. Heart Assoc. 2021, 10, e022277. [Google Scholar] [CrossRef]
  59. Liu, H.; Mao, P.; Xie, C.; Xie, W.; Wang, M.; Jiang, H. Apolipoprotein E polymorphism and the risk of intracranial aneurysms in a Chinese population. BMC Neurol. 2016, 16, 14. [Google Scholar] [CrossRef]
  60. Caird, J.; Burke, M.; Roberts, G.; Brett, F.; Phillips, J.; Usher, D.; Bouchier-Hayes, D.; Farrell, M. Apolipoprotein(A) expression in intracranial aneurysms. Neurosurgery 2003, 52, 854–859. [Google Scholar] [CrossRef]
  61. Phillips, J.; Roberts, G.; Bolger, C.; el Baghdady, A.; Bouchier-Hayes, D.; Farrell, M.; Collins, P. Lipoprotein (a): A potential biological marker for unruptured intracranial aneurysms. Neurosurgery 1997, 40, 1112–1117. [Google Scholar] [CrossRef]
  62. Bolger, C.; Phillips, J.; Gilligan, S.; Zourob, T.; Farrell, M.; Croake, D.; Collins, P.; Bouchier-Hayes, D. Elevated levels of lipoprotein (a) in association with cerebrovascular saccular aneurysmal disease. Neurosurgery 1995, 37, 241–245. [Google Scholar] [CrossRef]
  63. Roberts, G.A.; Corcoran, B.T.; Pfouts, L.L.; Phillips, J.P.; Farrell, M.A.; Bouchier-Hayes, D.J.; Collins, P.B. Genetic evaluation of lipoprotein(a) in intracranial aneurysm disease. Neurosurgery 2001, 49, 133–142. [Google Scholar]
  64. Synowiec, E.; Wojcik, K.A.; Wójcik, R.; Wiśniewski, K.; Fila, M.; Tokarz, P.; Bieńkowski, M.; Jaskolski, D.; Blasiak, J. Expression and variability of lipid metabolism genes in intracranial aneurysm. Cell Mol. Biol. 2016, 62, 73–82. [Google Scholar] [PubMed]
  65. van ‘t Hof, F.N.G.; Ruigrok, Y.M.; Baas, A.F.; Kiemeney, L.A.L.M.; Vermeulen, S.H.; Uitterlinden, A.G.; Hofman, A.; Rivadeneira, F.; Rinkel, G.J.E.; de Bakker, P.I.W. Impact of inherited genetic variants associated with lipid profile, hypertension, and coronary artery disease on the risk of intracranial and abdominal aortic aneurysms. Circ. Cardiovasc. Genet. 2013, 6, 264–270. [Google Scholar] [CrossRef] [PubMed]
  66. Takeda, R.; Islam, A.; Sato, T.; Kurita, H.; Kahyo, T.; Urano, T.; Setou, M. The stability of the metabolic turnover of arachidonic acid in human unruptured intracranial aneurysmal walls is sustained. Clin. Neurol. Neurosurg. 2021, 208, 106881. [Google Scholar] [CrossRef] [PubMed]
  67. Ollikainen, E.; Tulamo, R.; Lehti, S.; Lee-Rueckert, M.; Hernesniemi, J.; Niemelä, M.; Ylä-Herttuala, S.; Kovanen, P.T.; Frösen, J. Smooth Muscle Cell Foam Cell Formation, Apolipoproteins, and ABCA1 in Intracranial Aneurysms: Implications for Lipid Accumulation as a Promoter of Aneurysm Wall Rupture. J. Neuropathol. Exp. Neurol. 2016, 75, 689–699. [Google Scholar] [CrossRef]
  68. Ishii, D.; Matsushige, T.; Sakamoto, S.; Shimonaga, K.; Akiyama, Y.; Okazaki, T.; Oshita, J.; Kurisu, K. Decreased Antiatherogenic Protein Levels are Associated with Aneurysm Structure Alterations in MR Vessel Wall Imaging. J. Stroke Cerebrovasc. Dis. 2019, 28, 2221–2227. [Google Scholar] [CrossRef]
  69. Quan, K.; Song, J.; Yang, Z.; Wang, D.; An, Q.; Huang, L.; Liu, P.; Li, P.; Tian, Y.; Zhou, L.; et al. Validation of Wall Enhancement as a New Imaging Biomarker of Unruptured Cerebral Aneurysm. Stroke 2019, 50, 1570–1573. [Google Scholar] [CrossRef]
  70. Ishii, D.; Zanaty, M.; Roa, J.A.; Li, L.; Lu, Y.; Sabotin, R.; Allan, L.; Samaniego, E.A.; Hasan, D.M. Concentration of Lp(a) (Lipoprotein[a]) in Aneurysm Sac Is Associated With Wall Enhancement of Unruptured Intracranial Aneurysm. Stroke 2021, 52, 1465–1468. [Google Scholar] [CrossRef]
  71. Shimizu, K.; Miyata, H.; Abekura, Y.; Oka, M.; Kushamae, M.; Kawamata, T.; Mizutani, T.; Kataoka, H.; Nozaki, K.; Miyamoto, S.; et al. High-Fat Diet Intake Promotes the Enlargement and Degenerative Changes in the Media of Intracranial Aneurysms in Rats. J. Neuropathol. Exp. Neurol. 2019, 78, 798–807. [Google Scholar] [CrossRef]
  72. Jin, T.; Wang, L.; Li, D.; Yang, T.; Zhou, Y. Testosterone aggravates cerebral vascular injury by reducing plasma HDL levels. Open Life Sci. 2020, 15, 1042–1048. [Google Scholar] [CrossRef] [PubMed]
  73. Seifert, V.; Stolke, D.; Kaever, V.; Dietz, H. Arachidonic acid metabolism following aneurysm rupture. Evaluation of cerebrospinal fluid and serum concentration of 6-keto-prostaglandin F1 alpha and thromboxane B2 in patients with subarachnoid hemorrhage. Surg. Neurol. 1987, 27, 243–252. [Google Scholar] [CrossRef] [PubMed]
  74. Nonaka, N.; Matsukado, Y.; Oribe, Y.; Sano, Y.; Ito, Y.; Kuratsu, J.; Seto, H.; Miura, G. Lipids metabolism of the patients with subarachnoid hemorrhage due to ruptured intracranial aneurysm, in comparison with other cerebrovascular diseases. No Shinkei 1984, 36, 389–395. [Google Scholar]
  75. Seifert, V.; Stolke, D.; Kaever, V.; Dietz, H. Arachidonic acid metabolism following aneurysm rupture. Eur. Arch. Psychiatry Neurol. Sci. 1986, 236, 94–101. [Google Scholar] [CrossRef]
  76. Gaetani, P.; Marzatico, F.; Rodriguez y Baena, R. Ex vivo release of eicosanoids after aneurysmal subarachnoid hemorrhage: A preliminary experience in humans. Acta Neurol. Scand. 1992, 86, 184–189. [Google Scholar] [CrossRef]
  77. Jarocka-Karpowicz, I.; Syta-Krzyżanowska, A.; Kochanowicz, J.; Mariak, Z.D. Clinical Prognosis for SAH Consistent with Redox Imbalance and Lipid Peroxidation. Molecules 2020, 25, 1921. [Google Scholar] [CrossRef]
  78. Paoletti, P.; Gaetani, P.; Grignani, G.; Pacchiarini, L.; Silvani, V.; Rodriguez y Baena, R. CSF leukotriene C4 following subarachnoid hemorrhage. J. Neurosurg. 1988, 69, 488–493. [Google Scholar] [CrossRef]
  79. Asaeda, M.; Sakamoto, M.; Kurosaki, M.; Tabuchi, S.; Kamitani, H.; Yokota, M.; Watanabe, T. A non-enzymatic derived arachidonyl peroxide, 8-iso-prostaglandin F2 alpha, in cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage participates in the pathogenesis of delayed cerebral vasospasm. Neurosci. Lett. 2005, 373, 222–225. [Google Scholar] [CrossRef]
  80. Nam, D.H.; Kim, J.S.; Hong, S.C.; Lee, W.H.; Lee, J.I.; Shin, H.J.; Park, K.; Eoh, W.; Han, D.H.; Kim, J.H. Expression of interleukin-1 beta in lipopolysaccharide stimulated monocytes derived from patients with aneurysmal subarachnoid hemorrhage is correlated with cerebral vasospasm. Neurosci. Lett. 2001, 312, 41–44. [Google Scholar] [CrossRef]
  81. Kamezaki, T.; Yanaka, K.; Nagase, S.; Fujita, K.; Kato, N.; Nose, T. Increased levels of lipid peroxides as predictive of symptomatic vasospasm and poor outcome after aneurysmal subarachnoid hemorrhage. J. Neurosurg. 2002, 97, 1302–1305. [Google Scholar] [CrossRef]
  82. Sano, K.; Asano, T.; Tanishima, T.; Sasaki, T. Lipid peroxidation as a cause of cerebral vasospasm. Neurol. Res. 1980, 2, 253–272. [Google Scholar] [CrossRef]
  83. Promyslov, M.S.; Levchenko, L.I.; Demchuk, M.L.; Miakota, A.E. Lipid peroxidation of the cerebrospinal fluid in patients with arterial cerebral aneurysms. Zhurnal Vopr. Neirokhirurgii Im. NN Burdenko 1991, 3, 27–29. [Google Scholar]
  84. Rodriguez y Baena, R.; Gaetani, P.; Folco, G.; Viganó, T.; Paoletti, P. Arachidonate metabolites and vasospasm after subarachnoid haemorrhage. Neurol. Res. 1986, 8, 25–32. [Google Scholar] [CrossRef]
  85. Guo, Z.-D.; Sun, X.-C.; Zhang, J.H. The role of apolipoprotein e in the pathological events following subarachnoid hemorrhage: A review. Acta Neurochirurgica. Suppl. 2011, 110 Pt 2, 5–7. [Google Scholar] [CrossRef]
  86. Tang, J.; Zhao, J.; Zhao, Y.; Wang, S.; Chen, B.; Zeng, W. Apolipoprotein E epsilon4 and the risk of unfavorable outcome after aneurysmal subarachnoid hemorrhage. Surg. Neurol. 2003, 60, 391–396. [Google Scholar] [CrossRef]
  87. Leung, C.H.S.; Poon, W.S.; Yu, L.M.; Wong, G.K.C.; Ng, H.K. Apolipoprotein e genotype and outcome in aneurysmal subarachnoid hemorrhage. Stroke 2002, 33, 548–552. [Google Scholar] [CrossRef] [PubMed]
  88. Juvela, S.; Siironen, J.; Lappalainen, J. Apolipoprotein E genotype and outcome after aneurysmal subarachnoid hemorrhage. J. Neurosurg. 2009, 110, 989–995. [Google Scholar] [CrossRef] [PubMed]
  89. Dunn, L.T.; Stewart, E.; Murray, G.D.; Nicoll, J.A.; Teasdale, G.M. The influence of apolipoprotein E genotype on outcome after spontaneous subarachnoid hemorrhage: A preliminary study. Neurosurgery 2001, 48, 1006–1011. [Google Scholar] [PubMed]
  90. Huang, Q.; Shang-Guan, H.-C.; Wu, S.-Y.; Yao, P.-S.; Sun, Y.; Zeng, Y.-L.; Zheng, S.-F.; Chen, G.-R.; Lin, Y.-X.; Kang, D.-Z. High-Density Lipoprotein Is Associated with Progression of Intracranial Aneurysms. World Neurosurg. 2018, 120, e234–e240. [Google Scholar] [CrossRef]
  91. Syta-Krzyżanowska, A.; Jarocka-Karpowicz, I.; Kochanowicz, J.; Turek, G.; Rutkowski, R.; Gorbacz, K.; Mariak, Z.; Skrzydlewska, E. F2-isoprostanes and F4-neuroprostanes as markers of intracranial aneurysm development. Adv. Clin. Exp. Med. 2018, 27, 673–680. [Google Scholar] [CrossRef]
  92. Wiśniewski, K.; Jóźwik-Pruska, J.; Bieńkowski, M.; Bobeff, E.J.; Bryl, M.; Kałużna-Czaplińska, J.; Jaskólski, D.J. Isoprostanes as potential cerebral vasospasm biomarkers. Neurol. I Neurochir. Pol. 2018, 52, 643–651. [Google Scholar] [CrossRef] [PubMed]
  93. Li, B.; McIntyre, M.; Gandhi, C.; Halabi, M.; Long, A.; Van Hoof, A.; Afridi, A.; Schmidt, M.; Cole, C.; Santarelli, J.; et al. Low total cholesterol and high density lipoprotein are independent predictors of poor outcomes following aneurysmal subarachnoid hemorrhage: A preliminary report. Clin. Neurol. Neurosurg. 2020, 197, 106062. [Google Scholar] [CrossRef] [PubMed]
  94. Winking, M.; Müller, H.W.; Deinsberger, W.; Joedicke, A.; Boeker, D.K. Levels of immunoreactive cysteinyl-leukotrienes in CSF after subarachnoid haemorrhage correlate with blood flow-velocity in TCD. Acta Neurochir. 1997, 139, 764–769. [Google Scholar] [CrossRef]
  95. Aoki, T.; Kataoka, H.; Ishibashi, R.; Nozaki, K.; Hashimoto, N. Simvastatin suppresses the progression of experimentally induced cerebral aneurysms in rats. Stroke 2008, 39, 1276–1285. [Google Scholar] [CrossRef]
  96. Liu, P.; An, Q.; Chen, X.; Huang, J.; Yang, G.-Y.; Zhu, W. Rosuvastatin for enhancement of aneurysm neck endothelialization after coil embolization: Promotion of endothelial progenitor cells in a rodent model. J. Neurosurg. 2016, 124, 1265–1274. [Google Scholar] [CrossRef] [PubMed]
  97. Wei, H.; Yang, M.; Yu, K.; Dong, W.; Liang, W.; Wang, Z.; Jiang, R.; Zhang, J. Atorvastatin Protects Against Cerebral Aneurysmal Degenerative Pathology by Promoting Endothelial Progenitor Cells (EPC) Mobilization and Attenuating Vascular Deterioration in a Rat Model. Med. Sci. Monit. 2019, 25, 928–936. [Google Scholar] [CrossRef]
  98. Tseng, M.-Y.; Czosnyka, M.; Richards, H.; Pickard, J.D.; Kirkpatrick, P.J. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: A phase II randomized placebo-controlled trial. Stroke 2005, 36, 1627–1632. [Google Scholar] [CrossRef]
  99. Chen, J.; Li, M.; Zhu, X.; Chen, L.; Yang, S.; Zhang, C.; Wu, T.; Feng, X.; Wang, Y.; Chen, Q. Atorvastatin reduces cerebral vasospasm and infarction after aneurysmal subarachnoid hemorrhage in elderly Chinese adults. Aging 2020, 12, 2939–2951. [Google Scholar] [CrossRef]
  100. Akhigbe, T.; Zolnourian, A.; Bulters, D. Cholesterol-Reducing Agents for Treatment of Aneurysmal Subarachnoid Hemorrhage: Systematic Review and Meta-Analysis of Randomized Controlled Trials. World Neurosurg. 2017, 101, 476–485. [Google Scholar] [CrossRef]
  101. Tseng, M.-Y.; Hutchinson, P.J.; Turner, C.L.; Czosnyka, M.; Richards, H.; Pickard, J.D.; Kirkpatrick, P.J. Biological effects of acute pravastatin treatment in patients after aneurysmal subarachnoid hemorrhage: A double-blind, placebo-controlled trial. J. Neurosurg. 2007, 107, 1092–1100. [Google Scholar] [CrossRef] [PubMed]
  102. Kramer, A.H.; Gurka, M.J.; Nathan, B.; Dumont, A.S.; Kassell, N.F.; Bleck, T.P. Statin use was not associated with less vasospasm or improved outcome after subarachnoid hemorrhage. Neurosurgery 2008, 62, 422–430. [Google Scholar] [CrossRef]
  103. Vergouwen, M.D.I.; Meijers, J.C.M.; Geskus, R.B.; Coert, B.A.; Horn, J.; Stroes, E.S.G.; van der Poll, T.; Vermeulen, M.; Roos, Y.B.W.E.M. Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: A double-blind, placebo-controlled randomized trial. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2009, 29, 1444–1453. [Google Scholar] [CrossRef]
  104. McGirt, M.J.; Garces Ambrossi, G.L.; Huang, J.; Tamargo, R.J. Simvastatin for the prevention of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage: A single-institution prospective cohort study. J. Neurosurg. 2009, 110, 968–974. [Google Scholar] [CrossRef] [PubMed]
  105. Sanchez-Peña, P.; Nouet, A.; Clarençon, F.; Colonne, C.; Jean, B.; Le Jean, L.; Fonfrede, M.; Aout, M.; Vicaut, E.; Puybasset, L. Atorvastatin decreases computed tomography and S100-assessed brain ischemia after subarachnoid aneurysmal hemorrhage: A comparative study. Crit. Care Med. 2012, 40, 594–602. [Google Scholar] [CrossRef]
  106. Naraoka, M.; Matsuda, N.; Shimamura, N.; Asano, K.; Akasaka, K.; Takemura, A.; Hasegawa, S.; Ohkuma, H. Long-acting statin for aneurysmal subarachnoid hemorrhage: A randomized, double-blind, placebo-controlled trial. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2018, 38, 1190–1198. [Google Scholar] [CrossRef] [PubMed]
  107. Li, W.; Zhang, Y.; Tian, Z.; Zhu, W.; Liu, J.; Zhang, Y.; Yang, X.; Tian, D.-C. Statin treatment for unruptured intracranial aneurysms study: A study protocol for a double-blind, placebo-controlled trial. Stroke Vasc. Neurol. 2020, 5, 410–415. [Google Scholar] [CrossRef]
  108. Wang, J.; Weng, J.; Li, H.; Jiao, Y.; Fu, W.; Huo, R.; Yan, Z.; Xu, H.; Zhan, J.; Wang, S.; et al. Atorvastatin and growth, rupture of small unruptured intracranial aneurysm: Results of a prospective cohort study. Ther. Adv. Neurol. Disord. 2021, 14, 1756286420987939. [Google Scholar] [CrossRef]
  109. Turhon, M.; Kang, H.; Huang, J.; Li, M.; Liu, J.; Zhang, Y.; Wang, K.; Yang, X.; Zhang, Y. Atorvastatin for unruptured intracranial vertebrobasilar dissecting aneurysm (ATREAT-VBD): Protocol for a randomised, double-blind, blank-controlled trial. BMJ Open 2022, 12, e059616. [Google Scholar] [CrossRef]
  110. Kang, H.; Tian, D.-C.; Yang, X.; Zhang, Y.; Li, W.; Sui, B.; Duan, Y.; Zhang, Y.; Liu, J.; Wang, K.; et al. A Randomized Controlled Trial of Statins to Reduce Inflammation in Unruptured Cerebral Aneurysms. JACC. Cardiovasc. Imaging 2022, 15, 1668–1670. [Google Scholar] [CrossRef]
  111. Yoneda, H.; Shirao, S.; Kurokawa, T.; Fujisawa, H.; Kato, S.; Suzuki, M. Does eicosapentaenoic acid (EPA) inhibit cerebral vasospasm in patients after aneurysmal subarachnoid hemorrhage? Acta Neurol. Scand. 2008, 118, 54–59. [Google Scholar] [CrossRef] [PubMed]
  112. Yoneda, H.; Shirao, S.; Nakagawara, J.; Ogasawara, K.; Tominaga, T.; Suzuki, M. A prospective, multicenter, randomized study of the efficacy of eicosapentaenoic acid for cerebral vasospasm: The EVAS study. World Neurosurg. 2014, 81, 309–315. [Google Scholar] [CrossRef]
  113. Nakagawa, I.; Yokoyama, S.; Omoto, K.; Takeshima, Y.; Matsuda, R.; Nishimura, F.; Yamada, S.; Yokota, H.; Motoyama, Y.; Park, Y.-S.; et al. ω-3 Fatty Acids Ethyl Esters Suppress Cerebral Vasospasm and Improve Clinical Outcome Following Aneurysmal Subarachnoid Hemorrhage. World Neurosurg. 2017, 99, 457–464. [Google Scholar] [CrossRef] [PubMed]
  114. Abekura, Y.; Ono, I.; Kawashima, A.; Takizawa, K.; Koseki, H.; Miyata, H.; Shimizu, K.; Oka, M.; Kushamae, M.; Miyamoto, S.; et al. Eicosapentaenoic acid prevents the progression of intracranial aneurysms in rats. J. Neuroinflammation 2020, 17, 129. [Google Scholar] [CrossRef] [PubMed]
Biomolecules 13 01652 g001
Figure 1. Intracranial aneurysms are influenced by LMD at different stages of their development and rupture (a–d).
Figure 1. Intracranial aneurysms are influenced by LMD at different stages of their development and rupture (a–d).
Biomolecules 13 01652 g001
Table 1. Basic characteristics of enrolled clinical trials and subjects.
Table 1. Basic characteristics of enrolled clinical trials and subjects.
ReferencesSample Size (E/C)Diagnosis StandardExperimental GroupControl GroupTreatment DurationOutcome Measures
Tseng MY et al., 2005 [98]40/40 aSAHCTPravastatin 40 mg/dPlacebo14 dPostoperative complications (cerebral vasospasm, cerebral autoregulation, vasospasm-related DID)
Tseng MY et al., 2007 [101]38/42 aSAHCT/DSAPravastatin 40 mg/dPlacebo14 dLaboratory parameters, postoperative complications (DIND), clinical symptom scores (6-month mRS)
Kramer AH et al., 2008 [102]71/79 aSAHCT/CTA/DSASimvastatin 80 mg/dNonstatin14 dPostoperative complications (cerebral vasospasm, delayed infarction), clinical symptom scores (GOS of 1 to 3)
Vergouwen MD et al., 2009 [103]16/16 aSAHCT/CTASimvastatin 80 mg/dPlacebo15 dLaboratory parameters, postoperative complications, and clinical symptom scores (3- and 6-month GOS after SAH)
McGirt MJ et al., 2009 [104]170/170 aSAHCT/CTA/DSASimvastatin 80 mg/dNonstatin14 dPostoperative complications (cerebral vasospasm) and clinical symptom scores (perioperative death, length of hospital stay, discharged GOS)
Sanchez-Peña P et al., 2012 [105]142/136 aSAHCT/DSAAtorvastatin 40 mg/dNonstatin21 dClinical symptom scores (discharged and 1-yr GOS and modified Rankin Scale)
Naraoka M et al., 2018 [106]54/54 aSAHCTPitavastatin 4 mg/dPlacebo14 dPostoperative complications (DIND, cerebral vasospasm, vasospasm-related new cerebral infarctions)
Chen J et al., 2020 [99]150/150 aSAHCT/CTA/DSAAtorvastatin 20 mg/dPlacebo14 dPostoperative complications (CVS, infarction, DIND) and clinical symptom scores (6-month GOS after SAH, 30-day mortality)
Li W et al., 2020 [107]30/30 UIACTA/MRA/DSA/HR-MRIAtorvastatin 20 mg/dPlacebo12 MAWE, aneurysm morphology, inflammatory factors (CRP, TNF-α, IL-1β, and IL-6)
Wang J et al., 2021 [108]489/598 UIACTA/MRA/DSAAtorvastatin 20 mg/dNonstatin3 yrsAneurysm rupture (confirmed with CT or MRI)
Turhon M et al., 2022 [109]20/20 UIACTA/MRA/DSA/HR-MRIAtorvastatin 20 mg/dNonstatin6 MAWE, aneurysm morphology, inflammatory factors (CRP, TNF-α, IL-1β, and IL-6)
Kang H et al., 2022 [110]30/30 UIAVW-MRIAtorvastatin 20 mg/dPlacebo6 MWEI, 3D-WEVR, aneurysm morphology, inflammatory factors
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Pan, T.; Shi, Y.; Yu, G.; Mamtimin, A.; Zhu, W. Intracranial Aneurysms and Lipid Metabolism Disorders: From Molecular Mechanisms to Clinical Implications. Biomolecules 2023, 13, 1652. https://doi.org/10.3390/biom13111652

AMA Style

Pan T, Shi Y, Yu G, Mamtimin A, Zhu W. Intracranial Aneurysms and Lipid Metabolism Disorders: From Molecular Mechanisms to Clinical Implications. Biomolecules. 2023; 13(11):1652. https://doi.org/10.3390/biom13111652

Chicago/Turabian Style

Pan, Tonglin, Yuan Shi, Guo Yu, Abdureshid Mamtimin, and Wei Zhu. 2023. "Intracranial Aneurysms and Lipid Metabolism Disorders: From Molecular Mechanisms to Clinical Implications" Biomolecules 13, no. 11: 1652. https://doi.org/10.3390/biom13111652

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