Emerging Circulating Biomarkers in Atherosclerosis: From Molecular Mechanisms to Therapeutic Strategies

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 29610

Special Issue Editors


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Guest Editor
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Interests: inherited dyslipidemia; lipid lowering therapies; type 2 diabetes; coronary artery calcium score

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Guest Editor
Diabetes and Islet Transplantation Unit, Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC Italy, Palermo, Italy
Interests: diabetes; metabolism; cardiovascular prevention; dyslipidemia; nonalcoholic steatohepatitis

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Guest Editor
Senior Assistant Professor of Internal Medicine, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
Interests: atherosclerosis; endothelial function; lipids; cardiovascular biomarkers

Special Issue Information

Dear Colleagues,

Atherosclerosis is a long-term damaging process, and its progression leads to cardiovascular system injury. Several environmental and genetic factors play a part in atherosclerosis progression; among these, an increased plasma amount of low-density lipoprotein (LDL) cholesterol (LDL-C) is causatively associated with atherosclerotic cardiovascular disease (ASCVD). However, the full definition of atherosclerosis such as a chronic deposition of LDL-C may be not exhaustive; in fact, other processes are involved in the pathogenesis and progression of atherosclerosis together with LDL cholesterol. In the last few years, several studies have indicated the importance of the inflammatory state in the pathophysiology of ASCVD; in particular, inflammation appears to be the final expression of the systemic interaction between the amount of cholesterol and the immune system during atherosclerosis progression. In subjects with dyslipidemia, previous studies have shown that lipid storage in the arterial wall promotes the inflammatory cascade and thus the migration of immune cells, such as monocyte-derived macrophages and T lymphocyte subtypes, into the inflammatory lipid wall injury. The concept of atherosclerosis as a continuous inflammatory process promoted by a persistent amount of LDL-C and immune system activation may explain why, despite lifestyle changes and lipid-lowering treatments, ASCVD is still considered the leading cause of death and disease burden. In this context, novel circulating biomarkers may be helpful to better define the link between lipid metabolism, inflammation, and the immune system in the atherosclerotic process in the general population and, in particular, in subjects with a high risk of cardiovascular events.

This Special Issue will focus on the role of novel circulating biomarkers in atherosclerosis through the description of molecular mechanisms and the modulation of innovative therapies.

Dr. Roberto Scicali
Dr. Alessandro Mattina
Prof. Dr. Giuseppe Mandraffino
Guest Editors

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Keywords

  • atherosclerosis
  • lipids
  • inflammation
  • immunity
  • therapy

Published Papers (9 papers)

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Editorial

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3 pages, 195 KiB  
Editorial
Emerging Circulating Biomarkers in Atherosclerosis: From Molecular Mechanisms to Therapeutic Strategies
by Giuseppe Mandraffino, Alessandro Mattina and Roberto Scicali
Biomolecules 2022, 12(6), 809; https://doi.org/10.3390/biom12060809 - 9 Jun 2022
Viewed by 1279
Abstract
Atherosclerosis is a long-term damaging process, and its progression leads to cardiovascular system injury [...] Full article

Research

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12 pages, 1587 KiB  
Article
The Fibrinogen-like Domain of ANGPTL3 Facilitates Lipolysis in 3T3-L1 Cells by Activating the Intracellular Erk Pathway
by Simone Bini, Valeria Pecce, Alessia Di Costanzo, Luca Polito, Ameneh Ghadiri, Ilenia Minicocci, Federica Tambaro, Stella Covino, Marcello Arca and Laura D’Erasmo
Biomolecules 2022, 12(4), 585; https://doi.org/10.3390/biom12040585 - 16 Apr 2022
Cited by 7 | Viewed by 2360
Abstract
Background: ANGPTL3 stimulates lipolysis in adipocytes, but the underlying molecular mechanism is yet unknown. The C-terminal fibrinogen-like domain of ANGPTL3 (ANGPTL3-Fld) activates the AKT pathway in endothelial cells. Hence, we evaluated whether ANGPTL3-Fld stimulates lipolysis in adipocytes through the MAPK kinase pathway. Materials [...] Read more.
Background: ANGPTL3 stimulates lipolysis in adipocytes, but the underlying molecular mechanism is yet unknown. The C-terminal fibrinogen-like domain of ANGPTL3 (ANGPTL3-Fld) activates the AKT pathway in endothelial cells. Hence, we evaluated whether ANGPTL3-Fld stimulates lipolysis in adipocytes through the MAPK kinase pathway. Materials and Methods: 3T3-L1 adipocytes were treated with isoproterenol (ISO), ANGPTL3-Fld, or both. Lipolysis was evaluated through the release of free fatty acids (FFAs) in the culture medium. The activation status of intracellular kinases was evaluated with and without the inhibition of the BRAF–ERK arm of the MAPK pathway. Results: ANGPTL3-Fld alone was not able to activate lipolysis, while the combination of ANGPTL3-Fld and ISO determined a 10-fold enrichment of the FFA concentration in the culture medium with an incremental effect (twofold) when compared with ISO alone. ANGPTL3-Fld alone inhibited hormone-sensitive lipase (HSL), whereas the treatment with ISO induced the activation of HSL. The net balance of ANGPTL3-Fld and ISO cotreatment resulted in HSL activation. The results indicate that ANGPTL3-Fld generated an intracellular activation signal involving the MAPK–ERK pathway, possibly through the PDGFRβ—PLCγ-AMPK axis. Conclusion: ANGPTL3-Fld appears to act as a facilitator of lipolysis in adipocytes, and this effect was driven by a signal mediated by a pathway that is different from the canonical β-adrenergic stimulus. Full article
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13 pages, 664 KiB  
Article
PCSK9 Plasma Levels Are Associated with Mechanical Vascular Impairment in Familial Hypercholesterolemia Subjects without a History of Atherosclerotic Cardiovascular Disease: Results of Six-Month Add-On PCSK9 Inhibitor Therapy
by Arianna Toscano, Maria Cinquegrani, Michele Scuruchi, Antonino Di Pino, Salvatore Piro, Viviana Ferrara, Carmela Morace, Alberto Lo Gullo, Egidio Imbalzano, Francesco Purrello, Giovanni Squadrito, Roberto Scicali and Giuseppe Mandraffino
Biomolecules 2022, 12(4), 562; https://doi.org/10.3390/biom12040562 - 9 Apr 2022
Cited by 12 | Viewed by 1896
Abstract
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) metabolism involved in the degradation of the low-density lipoprotein receptor (LDLR) through complex mechanisms. The PCSK9 plasma levels change according to lipid lowering therapy (LLT). Few data exist regarding the [...] Read more.
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) metabolism involved in the degradation of the low-density lipoprotein receptor (LDLR) through complex mechanisms. The PCSK9 plasma levels change according to lipid lowering therapy (LLT). Few data exist regarding the role of PCSK9 in vascular damage. We aimed to evaluate the impact of PCSK9 plasma levels on pulse wave velocity (PWV) and the effect of PCSK9 inhibitors (PCSK9-i) on circulating PCSK9 and PWV in a cohort of heterozygous familial hypercholesterolemia (HeFH) subjects. In a previous step, HeFH patients were enrolled and LLT was prescribed according to guidelines. Biochemical analyses and PWV assessment were performed at baseline (T0), after 6 months of high-efficacy statin plus ezetimibe (T1) and after 6 months of PCSK9-i (T2). The PCSK9 levels were evaluated in 26 selected HeFH subjects at the three time points and 26 healthy subjects served as controls for the reference value for PCSK9 plasma levels. The PWV values decreased at each time point in HeFH subjects after LLT starting (8.61 ± 2.4 m/s, −8.7%; p < 0.001 vs. baseline at T1, and 7.9 ± 2.1 m/s, −9.3%; p < 0.001 vs. both T1 and baseline) and it was correlated to PCSK9 (r = 0.411, p = 0.03). The PCSK9 levels increased on statin/EZE therapy (+42.8% at T1) while it decreased after PCSK9-i was started (−34.4% at T2). We noted a significant relationship between PCSK9 levels and PWV changes at T1 and T2. In conclusion, PCSK9 levels were associated with baseline PWV values in HeFH subjects; moreover, we found that PCSK9 level variations seemed to be correlated with PWV changes on LLT. A longer observation time and wider sample size are needed to assess the potential role of PCSK9 plasma levels on the vascular function and remodelling, and to clarify the effects of PCSK9-i in these pathways. Full article
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10 pages, 999 KiB  
Article
Characterization of the LPS and 3OHFA Contents in the Lipoprotein Fractions and Lipoprotein Particles of Healthy Men
by Pere Rehues, Marina Rodríguez, Judith Álvarez, Marta Jiménez, Alba Melià, Mar Sempere, Clara Balsells, Gemma Castillejo, Montse Guardiola, Antoni Castro and Josep Ribalta
Biomolecules 2022, 12(1), 47; https://doi.org/10.3390/biom12010047 - 29 Dec 2021
Cited by 6 | Viewed by 1641
Abstract
Atherosclerosis is a chronic inflammatory disease that is caused by the accumulation of LDL particles in the intima, causing the activation of immune cells and triggering an inflammatory response. LPS is a potent activator of the innate immune response and it can be [...] Read more.
Atherosclerosis is a chronic inflammatory disease that is caused by the accumulation of LDL particles in the intima, causing the activation of immune cells and triggering an inflammatory response. LPS is a potent activator of the innate immune response and it can be transported by lipoproteins. Since humans are much more sensitive to LPS than other mammals, and very low amounts of LPS can elicit an immune response, the aim of this study is to characterize the distribution of LPS and its immunogenic portion (3OHFAs) among lipoprotein types of healthy men. We separated lipoprotein fractions by ultracentrifugation and the amount of each 3OHFA was measured by MS in each lipoprotein fraction to calculate LPS concentration. Lipoprotein particle concentration was measured by NMR. LDL and HDL fractions transported the highest concentration of LPS (35.7% and 31.5%, respectively), but VLDL particles carried more LPS molecules per particle (0.55 molecules/particle) than LDL or HDL (p < 0.01). The distribution of LPS and all 3OHFAs among lipoprotein fractions showed high interindividual variability, suggesting that they may be studied as a potential biomarker. This may help understand the role of LPS in atherosclerosis in those cases where the disease cannot be explained by traditional risk factors. Full article
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15 pages, 653 KiB  
Article
Changes of Metabolic Biomarker Levels upon One-Year Anti-TNF-α Therapy in Rheumatoid Arthritis and Ankylosing Spondylitis: Associations with Vascular Pathophysiology
by Monika Czókolyová, Anita Pusztai, Edit Végh, Ágnes Horváth, Anita Szentpéteri, Attila Hamar, Szilvia Szamosi, Katalin Hodosi, Andrea Domján, Sándor Szántó, György Kerekes, Ildikó Seres, Mariann Harangi, György Paragh, Éva Szekanecz, Zoltán Szekanecz and Gabriella Szűcs
Biomolecules 2021, 11(10), 1535; https://doi.org/10.3390/biom11101535 - 18 Oct 2021
Cited by 10 | Viewed by 2755
Abstract
Background: Cardiovascular (CV) morbidity, mortality, and metabolic syndrome are associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Here, lipids and other metabolic markers in relation to vascular function and clinical markers were evaluated in RA and AS patients undergoing one-year anti-TNF therapy. [...] Read more.
Background: Cardiovascular (CV) morbidity, mortality, and metabolic syndrome are associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Here, lipids and other metabolic markers in relation to vascular function and clinical markers were evaluated in RA and AS patients undergoing one-year anti-TNF therapy. Patients and methods: Fifty-three patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Various lipids, paraoxonase (PON) and arylesterase (ARE) activities, myeloperoxidase (MPO) and adipokine levels were determined overtime. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV) in all patients. All assessments were performed at baseline and 6 and 12 months after treatment initiation. Results: Anti-TNF therapy decreased ARE activity, MPO, adiponectin, and chemerin levels after 12 months (p < 0.05). Lipids, PON activity, and leptin remained unchanged. Regression analyses suggested variable associations of IMT, PWV, and FMD with ARE, MPO, leptin, and lipids (p < 0.05). On the other hand, these metabolic parameters were significantly associated with disease duration, CV history, CRP, obesity, PWV, and IMT (p < 0.05). One-year anti-TNF treatment together with baseline leptin (p = 0.039) or CRP (p = 0.016) levels determined 12 months of lipid changes overtime. TNF inhibition together with baseline disease activity determined ARE activity changes (p = 0.046). Anti-TNF therapy and baseline chemerin levels determined IMT changes overtime (p = 0.003). Conclusions: Assessment of various metabolic parameters together with disease activity, CRP, and ultrasound-based techniques may exert additional value in determining CV burden and in monitoring the effects of biologics on preclinical vascular pathophysiology. Full article
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15 pages, 2751 KiB  
Article
Native Low-Density Lipoproteins Act in Synergy with Lipopolysaccharide to Alter the Balance of Human Monocyte Subsets and Their Ability to Produce IL-1 Beta, CCR2, and CX3CR1 In Vitro and In Vivo: Implications in Atherogenesis
by Aarón N. Manjarrez-Reyna, Camilo P. Martínez-Reyes, José A. Aguayo-Guerrero, Lucia A. Méndez-García, Marcela Esquivel-Velázquez, Sonia León-Cabrera, Gilberto Vargas-Alarcón, José M. Fragoso, Elizabeth Carreón-Torres, Oscar Pérez-Méndez, Jessica L. Prieto-Chávez and Galileo Escobedo
Biomolecules 2021, 11(8), 1169; https://doi.org/10.3390/biom11081169 - 7 Aug 2021
Cited by 3 | Viewed by 2355
Abstract
Increasing evidence has demonstrated that oxidized low-density lipoproteins (oxLDL) and lipopolysaccharide (LPS) enhance accumulation of interleukin (IL)-1 beta-producing macrophages in atherosclerotic lesions. However, the potential synergistic effect of native LDL (nLDL) and LPS on the inflammatory ability and migration pattern of monocyte subpopulations [...] Read more.
Increasing evidence has demonstrated that oxidized low-density lipoproteins (oxLDL) and lipopolysaccharide (LPS) enhance accumulation of interleukin (IL)-1 beta-producing macrophages in atherosclerotic lesions. However, the potential synergistic effect of native LDL (nLDL) and LPS on the inflammatory ability and migration pattern of monocyte subpopulations remains elusive and is examined here. In vitro, whole blood cells from healthy donors (n = 20) were incubated with 100 μg/mL nLDL, 10 ng/mL LPS, or nLDL + LPS for 9 h. Flow cytometry assays revealed that nLDL significantly decreases the classical monocyte (CM) percentage and increases the non-classical monocyte (NCM) subset. While nLDL + LPS significantly increased the number of NCMs expressing IL-1 beta and the C-C chemokine receptor type 2 (CCR2), the amount of NCMs expressing the CX3C chemokine receptor 1 (CX3CR1) decreased. In vivo, patients (n = 85) with serum LDL-cholesterol (LDL-C) >100 mg/dL showed an increase in NCM, IL-1 beta, LPS-binding protein (LBP), and Castelli’s atherogenic risk index as compared to controls (n = 65) with optimal LDL-C concentrations (≤100 mg/dL). This work demonstrates for the first time that nLDL acts in synergy with LPS to alter the balance of human monocyte subsets and their ability to produce inflammatory cytokines and chemokine receptors with prominent roles in atherogenesis. Full article
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Review

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14 pages, 1909 KiB  
Review
Lipoprotein(a)—The Crossroads of Atherosclerosis, Atherothrombosis and Inflammation
by Sabina Ugovšek and Miran Šebeštjen
Biomolecules 2022, 12(1), 26; https://doi.org/10.3390/biom12010026 - 24 Dec 2021
Cited by 34 | Viewed by 5419
Abstract
Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations [...] Read more.
Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of chromosome 6, within region 6q2.6–2.7. Lp(a) levels increase cardiovascular risk through several unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipoprotein cholesterol, although it is even more prone to oxidation and penetration through endothelia to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the homology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70% homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms of Lp(a) is predominant in different groups of patients. Full article
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16 pages, 1305 KiB  
Review
Integrative Analysis of Multi-Omics and Genetic Approaches—A New Level in Atherosclerotic Cardiovascular Risk Prediction
by EIena I. Usova, Asiiat S. Alieva, Alexey N. Yakovlev, Madina S. Alieva, Alexey A. Prokhorikhin, Alexandra O. Konradi, Evgeny V. Shlyakhto, Paolo Magni, Alberico L. Catapano and Andrea Baragetti
Biomolecules 2021, 11(11), 1597; https://doi.org/10.3390/biom11111597 - 28 Oct 2021
Cited by 13 | Viewed by 3207
Abstract
Genetics and environmental and lifestyle factors deeply affect cardiovascular diseases, with atherosclerosis as the etiopathological factor (ACVD) and their early recognition can significantly contribute to an efficient prevention and treatment of the disease. Due to the vast number of these factors, only the [...] Read more.
Genetics and environmental and lifestyle factors deeply affect cardiovascular diseases, with atherosclerosis as the etiopathological factor (ACVD) and their early recognition can significantly contribute to an efficient prevention and treatment of the disease. Due to the vast number of these factors, only the novel “omic” approaches are surmised. In addition to genomics, which extended the effective therapeutic potential for complex and rarer diseases, the use of “omics” presents a step-forward that can be harnessed for more accurate ACVD prediction and risk assessment in larger populations. The analysis of these data by artificial intelligence (AI)/machine learning (ML) strategies makes is possible to decipher the large amount of data that derives from such techniques, in order to provide an unbiased assessment of pathophysiological correlations and to develop a better understanding of the molecular background of ACVD. The predictive models implementing data from these “omics”, are based on consolidated AI best practices for classical ML and deep learning paradigms that employ methods (e.g., Integrative Network Fusion method, using an AI/ML supervised strategy and cross-validation) to validate the reproducibility of the results. Here, we highlight the proposed integrated approach for the prediction and diagnosis of ACVD with the presentation of the key elements of a joint scientific project of the University of Milan and the Almazov National Medical Research Centre. Full article
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17 pages, 1200 KiB  
Review
Cardiorenal Syndrome: New Pathways and Novel Biomarkers
by Guido Gembillo, Luca Visconti, Maria Ausilia Giusti, Rossella Siligato, Alessia Gallo, Domenico Santoro and Alessandro Mattina
Biomolecules 2021, 11(11), 1581; https://doi.org/10.3390/biom11111581 - 26 Oct 2021
Cited by 27 | Viewed by 5777
Abstract
Cardiorenal syndrome (CRS) is a multi-organ disease characterized by the complex interaction between heart and kidney during acute or chronic injury. The pathogenesis of CRS involves metabolic, hemodynamic, neurohormonal, and inflammatory mechanisms, and atherosclerotic degeneration. In the process of better understanding the bi-directional [...] Read more.
Cardiorenal syndrome (CRS) is a multi-organ disease characterized by the complex interaction between heart and kidney during acute or chronic injury. The pathogenesis of CRS involves metabolic, hemodynamic, neurohormonal, and inflammatory mechanisms, and atherosclerotic degeneration. In the process of better understanding the bi-directional pathophysiological aspects of CRS, the need to find precise and easy-to-use markers has also evolved. Based on the new pathophysiological standpoints and an overall vision of the CRS, the literature on renal, cardiac, metabolic, oxidative, and vascular circulating biomarkers was evaluated. Though the effectiveness of different extensively applied biomarkers remains controversial, evidence for several indicators, particularly when combined, has increased in recent years. From new aspects of classic biomarkers to microRNAs, this review aimed at a 360-degree analysis of the pathways that balance the kidney and the heart physiologies. In this delicate system, different markers and their combination can shed light on the diagnosis, risk, and prognosis of CRS. Full article
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