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Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 20946

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Dr. Nikita G. Nikiforov

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Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia
Interests: macrophage; monocyte; chronic inflammation; innate immunity; mitophagy; dysfunctional mitochondria; modified low density lipoprotein; atherosclerosis
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Dear Colleagues,

The modern inflammatory hypothesis of atherogenesis, which supplemented the classical cholesterol hypothesis, is now generally accepted and suggests the development of an effective therapy aimed at eliminating local chronic inflammation in the vessel wall. Thanks to Anichkov's cholesterol theory, it is well known that the accumulation of intracellular cholesterol in the vascular wall is a trigger for atherogenesis. However, not everything is so simple: approaches aimed at lowering blood cholesterol, LDL receptor regulation or cholesterol efflux showed insufficient effectiveness. However, they significantly improved the life expectancy and quality of life.

Recent advancements in new anti-inflammatory trials aiming to reduce cardiovascular complications only confirm the central role of chronic inflammation in CVD. Additionally, the importance of these trials can hardly be overestimated. The issue of uncovering the mechanisms underlying the chronification of the inflammatory response is now becoming especially urgent.

I think our current achievements are very similar to the success of physicists, hard at work on the Theory of Everything, which would explain the laws of the universe. Despite the complexity of our problem, I believe that humanity is already close to unraveling the underlying mechanisms of diseases, and we will be able to beat atherosclerosis, cancer, aging and, ultimately, death. However, then we will face completely different problems with the economy, overpopulation and other aspects.

In this Special Issue, I want to collect the most recent publications on the mechanisms of the initiation of atherosclerosis and other age-related diseases. Of course, studies on other important factors, such as lipid metabolism, genetic predisposition, the role of the microbiota, etc., as well as novel therapeutic approaches, are welcome. I also welcome research describing mitochondrial dysfunction, mtDNA mutations and role of mitochondria in immune response.

Dr. Nikita G. Nikiforov
Guest Editor

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Keywords

atherosclerosis
cardiovascular diseases
molecular and cellular mechanisms
chronic inflammation
innate immunity
mitochondrial dysfunction
aging
inflammaging

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

4 pages, 183 KiB

Open AccessEditorial

Editorial to the Special Issue “Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis”

by Nikita G. Nikiforov

Biomedicines 2024, 12(9), 2148; https://doi.org/10.3390/biomedicines12092148 - 23 Sep 2024

Viewed by 494

Abstract

The current Special Issue, “Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis”, is dedicated to exploring the various mechanisms involved in atherogenesis [...] Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

Research

Jump to: Editorial, Review

17 pages, 3175 KiB

Open AccessArticle

Intermediate Monocytes and Circulating Endothelial Cells: Interplay with Severity of Atherosclerosis in Patients with Coronary Artery Disease and Type 2 Diabetes Mellitus

by Irina V. Kologrivova, Tatiana E. Suslova, Olga A. Koshelskaya, Elena S. Kravchenko, Olga A. Kharitonova, Ekaterina A. Romanova, Alexandra I. Vyrostkova and Alla A. Boshchenko

Biomedicines 2023, 11(11), 2911; https://doi.org/10.3390/biomedicines11112911 - 27 Oct 2023

Cited by 1 | Viewed by 1267

Abstract

The aim was to investigate the association of monocyte heterogeneity and presence of circulating endothelial cells with the severity of coronary atherosclerosis in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). We recruited 62 patients with CAD, including 22 patients with DM2. The severity of atherosclerosis was evaluated using Gensini Score. Numbers of classical (CD14++CD16–), intermediate (CD14++CD16+), and non-classical (CD14+CD16++) monocyte subsets; circulating endothelial progenitor cells; and the presence of circulating endothelial cells were evaluated. Counts and frequencies of intermediate monocytes, but not glycaemia parameters, were associated with the severity of atherosclerosis in diabetic CAD patients (r_s = 0.689; p = 0.001 and r_s = 0.632; p = 0.002, respectively). Frequency of Tie2+ cells was lower in classical than in non-classical monocytes in CAD patients (p = 0.007), while in patients with association of CAD and T2DM, differences between Tie2+ monocytes subsets disappeared (p = 0.080). Circulating endothelial cells were determined in 100% of CAD+T2DM patients, and counts of CD14++CD16+ monocytes and concentration of TGF-β predicted the presence of circulating endothelial cells (sensitivity 92.3%; specificity 90.9%; AUC = 0.930). Thus, intermediate monocytes represent one of the key determinants of the appearance of circulating endothelial cells in all the patients with CAD, but are associated with the severity of atherosclerosis only in patients with association of CAD and T2DM. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

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12 pages, 294 KiB

Open AccessArticle

The Role of Polymorphism in the Endothelial Homeostasis and Vitamin D Metabolism Genes in the Severity of Coronary Artery Disease

by Anastasia Ponasenko, Anna Sinitskaya, Maxim Sinitsky, Maria Khutornaya and Olga Barbarash

Biomedicines 2023, 11(9), 2382; https://doi.org/10.3390/biomedicines11092382 - 25 Aug 2023

Cited by 3 | Viewed by 1195

Abstract

Coronary artery disease (CAD) remains one of the leading causes of cardiovascular morbidity and mortality worldwide. The maintenance of endothelial homeostasis and vitamin D metabolism play an important role in CAD pathogenesis. This study aimed to determine the association of endothelial homeostasis and vitamin D metabolism gene polymorphism with CAD severity. A total of 224 low-risk patients (SYNTAX score ≤ 31) and 36 high-risk patients (SYNTAX score > 31) were recruited for this study. The serum level of E-, L- and P-selectins; endothelin; eNOS; 25OH; and 1.25-dihydroxy vitamin D was measured using an enzyme-linked immunosorbent assay (ELISA). Polymorphic variants in SELE, SELP, SELPLG, END1, NOS3, VDR and GC were analyzed using a polymerase chain reaction (PCR). We found no differences in the serum levels of the studied markers between high- and low-risk patients. Three polymorphic variants associated with CAD severity were discovered: END1 rs3087459, END1 rs5370 and GC rs2298849 in the log-additive model. Moreover, we discovered a significantly decreased serum level of 1.25-dihydroxy vitamin D in high-risk CAD patients with the A/A–A/G genotypes of the rs2228570 polymorphism of the VDR gene, the A/A genotype of the rs7041 polymorphism of the GC gene and the A/A genotype of the rs2298849 polymorphism of the GC gene. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

11 pages, 697 KiB

Open AccessArticle

Leucine-Rich Alpha-2-Glycoprotein: A Novel Predictor of Diastolic Dysfunction

by Alexander Loch, Kok Leng Tan, Mahmoud Danaee, Iskandar Idris and Mei Li Ng

Biomedicines 2023, 11(3), 944; https://doi.org/10.3390/biomedicines11030944 - 20 Mar 2023

Cited by 1 | Viewed by 1979

Abstract

Leucine-rich α2-glycoprotein (LRG1) mediates cardiac fibrocyte activation. It is upregulated in inflammatory conditions, atherosclerosis, and fibrosis. Diastolic dysfunction (DD) is due to myocardial fibrosis. This cross-sectional study examined the relationship between LRG1 and DD. Patients with symptoms of chronic coronary ischemia were recruited. Patients with symptoms of overt heart failure, ejection fraction (EF) < 55%, impaired renal function, infection, and recent trauma were excluded from the study. Clinical parameters examined were SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) score, echocardiographic assessment, and LRG1 levels. Binary stepwise logistic regression was used to evaluate the association between LRG1 and DD. Receiver Operating Characteristic (ROC) analysis was used to determine optimal cut-off values and predictive performance of LRG1. A total of 94 patients were enrolled in the study, with 47 having a clinical diagnosis of DD. Plasma LRG1 was significantly (U = 417.00, p < 0.001) higher in the DD group (M = 14) compared to the No-DD group (M = 8) by Mann–Whitney U test. There were higher SYNTAX scores in the DD group (M = 24.5) compared with No-DD (M = 7). LRG1 had significant predictability of DD (OR = 1.32 (95% CI: 1.14–1.53)). The ROC showed an AUC = 0.89 (95% CI: 0.82–0.95). LRG1 had a 78% sensitivity (95% CI: 65.3–87.7) and 72.3% specificity (95% CI: 57.4–84.4) for predicting DD at a cut-off value of “9”. In conclusion, we identified LRG1 as a novel independent predictor of DD. Further studies are warranted to validate the utility of LRG1 in predicting DD. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

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21 pages, 1663 KiB

Open AccessArticle

Monocytic Cell Adhesion to Oxidised Ligands: Relevance to Cardiovascular Disease

by Robin N. Poston, Jenna Chughtai, Desara Ujkaj, Huguette Louis, David S. Leake and Dianne Cooper

Biomedicines 2022, 10(12), 3083; https://doi.org/10.3390/biomedicines10123083 - 30 Nov 2022

Cited by 4 | Viewed by 1827

Abstract

Atherosclerosis, the major cause of vascular disease, is an inflammatory process driven by entry of blood monocytes into the arterial wall. LDL normally enters the wall, and stimulates monocyte adhesion by forming oxidation products such as oxidised phospholipids (oxPLs) and malondialdehyde. Adhesion molecules that bind monocytes to the wall permit traffic of these cells. CD14 is a monocyte surface receptor, a cofactor with TLR4 forming a complex that binds oxidised phospholipids and induces inflammatory changes in the cells, but data have been limited for monocyte adhesion. Here, we show that under static conditions, CD14 and TLR4 are implicated in adhesion of monocytes to solid phase oxidised LDL (oxLDL), and also that oxPL and malondialdehyde (MDA) adducts are involved in adhesion to oxLDL. Similarly, monocytes bound to heat shock protein 60 (HSP60), but this could be through contaminating lipopolysaccharide. Immunohistochemistry on atherosclerotic human arteries demonstrated increased endothelial MDA adducts and HSP60, but endothelial oxPL was not detected. We propose that monocytes could bind to MDA in endothelial cells, inducing atherosclerosis. Monocytes and platelets synergized in binding to oxLDL, forming aggregates; if this occurs at the arterial surface, they could precipitate thrombosis. These interactions could be targeted by cyclodextrins and oxidised phospholipid analogues for therapy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

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11 pages, 1690 KiB

Open AccessArticle

Rapid Drop in Coronary Heart Disease Mortality in Czech Male Population—What Was Actually behind It?

by Rudolf Poledne, Anna Kralova, Hana Bartuskova, Karel Paukner, Sona Kauerova, Jiri Fronek, Vera Lanska and Ivana Kralova Lesna

Biomedicines 2022, 10(11), 2871; https://doi.org/10.3390/biomedicines10112871 - 9 Nov 2022

Cited by 1 | Viewed by 1617

Abstract

The high mortality of coronary heart disease (CHD) among Czech men—one of the highest worldwide—began to decline in 1991 soon after the abolition of government subsidies to all foodstuffs rich in animal fat. As participants in the WHO MONICA Project, we were able to analyze the CHD risk factors just before and after this major economic change. We had previously documented that the originally subsidized prices decreased animal fat consumption and consequently non-HDL cholesterol concentrations in the population. By the early 1990s, no progress had been made in the treatment of acute myocardial infarction, statins were unavailable as was not the currently more effective antihypertensive therapy. Our recent research proved a close relationship between cholesterolemia and proinflammatory macrophages in adipose tissue and accelerated macrophage polarization with increased palmitate and palmitoleate contents in cell membrane phospholipids. By contrast, the proportion of proinflammatory macrophages decreases with increasing presence of n-3 fatty acids in the cell membrane. The combination of non-HDL cholesterol drop and a decreased proportion of proinflammatory macrophages due to replacement of alimentary fat decreased CHD mortality immediately. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

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38 pages, 19300 KiB

Open AccessArticle

Role of Endothelial Regeneration and Overloading of Enterocytes with Lipids in Capturing of Lipoproteins by Basement Membrane of Rat Aortic Endothelium

by Irina S. Sesorova, Vitaly V. Sesorov, Pavel B. Soloviev, Konstantin Yu. Lakunin, Ivan D. Dimov and Alexander A. Mironov

Biomedicines 2022, 10(11), 2858; https://doi.org/10.3390/biomedicines10112858 - 8 Nov 2022

Cited by 7 | Viewed by 1775

Abstract

Atherosclerosis is a complex non-monogenic disease related to endothelial damage in elastic-type arteries and incorrect feeding. Here, using cryodamage of endothelial cells (ECs) of rat abdominal aorta, we examined the role of the EC basement membrane (BM) for re-endothelization endothelial regeneration and its ability to capture low density lipoproteins (LDLs). Regeneration of endothelium induced thickening of the ECBM. Secretion of the BM components occurred in the G2-phase. Multiple regenerations, as well as arterial hypertension and aging, also led to the thickening of the BM. Under these conditions, the speed of re-endothelialization increased. The thick BM captured more LDLs. LDLs formed after overloading of rats with lipids acquired higher affinity to the BM, presumably due to the prolonged transport of chylomicrons through neuraminidase-positive endo-lysosomes. These data provide new molecular and cellular mechanisms of atherogenesis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

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15 pages, 2339 KiB

Open AccessArticle

Identification of Key Genes and Pathways in Genotoxic Stress Induced Endothelial Dysfunction: Results of Whole Transcriptome Sequencing

by Maxim Sinitsky, Anna Sinitskaya, Daria Shishkova, Alexey Tupikin, Maxim Asanov, Maria Khutornaya, Marsel Kabilov and Anastasia Ponasenko

Biomedicines 2022, 10(9), 2067; https://doi.org/10.3390/biomedicines10092067 - 24 Aug 2022

Cited by 4 | Viewed by 2072

Abstract

Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide. Endothelial disfunction underlying the atherogenesis can be triggered by genotoxic stress in endothelial cells. In the presented research whole transcriptome sequencing (RNA-seq) of human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells in vitro exposed to 500 ng/mL mitomycin C (treatment group) or 0.9% NaCl (control group) was performed. Resulting to bioinformatic analysis, 56 upregulated differentially expressed genes (DEGs) and 6 downregulated DEGs with absolute fold change ≥ 2 and FDR p-value < 0.05 were selected in HCAEC exposed to mitomycin C compared to the control group; in HITAEC only one upregulated DEG was found. According to Gene Ontology enrichment analysis, DEGs in HCAEC were classified into 25 functional groups of biological processes, while in HITAEC we found no statistically significant (FDR p-value < 0.05) groups. The four largest groups containing more than 50% DEGs (“signal transduction”, “response to stimulus”, “biological regulation”, and “regulation of biological process”) were identified. Finally, candidate DEGs and pathways underlying the genotoxic stress induced endothelial disfunction have been discovered that could improve our understanding of fundamental basis of atherogenesis and help to justification of genotoxic stress as a novel risk factor for atherosclerosis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

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Review

Jump to: Editorial, Research

36 pages, 1395 KiB

Open AccessEditor’s ChoiceReview

Novel Oxidative Stress Biomarkers with Risk Prognosis Values in Heart Failure

by Mei Li Ng, Xu Ang, Kwan Yi Yap, Jun Jie Ng, Eugene Chen Howe Goh, Benjamin Bing Jie Khoo, Arthur Mark Richards and Chester Lee Drum

Biomedicines 2023, 11(3), 917; https://doi.org/10.3390/biomedicines11030917 - 15 Mar 2023

Cited by 20 | Viewed by 3876

Abstract

Oxidative stress (OS) is mediated by reactive oxygen species (ROS), which in cardiovascular and other disease states, damage DNA, lipids, proteins, other cellular and extra-cellular components. OS is both initiated by, and triggers inflammation, cardiomyocyte apoptosis, matrix remodeling, myocardial fibrosis, and neurohumoral activation. These have been linked to the development of heart failure (HF). Circulating biomarkers generated by OS offer potential utility in patient management and therapeutic targeting. Novel OS-related biomarkers such as NADPH oxidases (sNox2-dp, Nrf2), advanced glycation end-products (AGE), and myeloperoxidase (MPO), are signaling molecules reflecting pathobiological changes in HF. This review aims to evaluate current OS-related biomarkers and their associations with clinical outcomes and to highlight those with greatest promise in diagnosis, risk stratification and therapeutic targeting in HF. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

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19 pages, 1090 KiB

Open AccessReview

Inflammatory Mechanisms of Diabetes and Its Vascular Complications

by Lyudmila V. Nedosugova, Yuliya V. Markina, Leyla A. Bochkareva, Irina A. Kuzina, Nina A. Petunina, Irina Y. Yudina and Tatiana V. Kirichenko

Biomedicines 2022, 10(5), 1168; https://doi.org/10.3390/biomedicines10051168 - 18 May 2022

Cited by 37 | Viewed by 3608

Abstract

The main cause of death in patients with type 2 DM is cardiovascular complications resulting from the progression of atherosclerosis. The pathophysiology of the association between diabetes and its vascular complications is complex and multifactorial and closely related to the toxic effects of hyperglycemia that causes increased generation of reactive oxygen species and promotes the secretion of pro-inflammatory cytokines. Subsequent oxidative stress and inflammation are major factors of the progression of type 2 DM and its vascular complications. Data on the pathogenesis of the development of type 2 DM and associated cardiovascular diseases, in particular atherosclerosis, open up broad prospects for the further development of new diagnostic and therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis)

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