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Atherosclerosis 2.0: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 November 2024) | Viewed by 13669

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Dr. Antonio Barbato

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Department of Clinical Medicine and Surgery, Federico II University of Naples Medical School, 80131 Naples, Italy
Interests: blood pressure; cardiovascular disease; metabolic syndrome; hypertension; atherosclerosis; cardiovascular epidemiology; metabolism; metabolic diseases; abdominal obesity; internal medicine
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Dear Colleagues,

Atherosclerosis is a common condition of vascular aging. However, several factors could influence this process, resulting in increased cardiovascular risk at a young age.

In addition to well-known factors (e.g., high blood pressure, dyslipidemia, diabetes, and excess body weight), there are several emerging factors associated with atherosclerosis such as inflammation, endothelial dysfunction, intestinal microbiota alteration, uric acid, vitamin D, or miRNA expression that could potentially explain the residual cardiovascular risk.

This Special Issue on atherosclerosis aims to report the most current scientific evidence available on this topic and present reviews of the current literature on the role of emerging factors in the development of atherosclerosis, as demonstrated by both experimental and clinical studies, in order to gather a large body of data from which to start to highlight new potential objectives for the reduction in cardiovascular risk.

Dr. Antonio Barbato
Guest Editor

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Keywords

atherosclerosis
cardiovascular risk
arterial stiffness
blood pressure
vitamin D
miRNA
inflammation

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Published Papers (8 papers)

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Research

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27 pages, 9468 KiB

Open AccessArticle

Phenotypic, Metabolic, and Functional Characterization of Experimental Models of Foamy Macrophages: Toward Therapeutic Research in Atherosclerosis

by Amina Sarah Henni Mansour, Mathilde Ragues, Julien Brevier, Coraline Borowczyk, Janaïna Grevelinger, Jeanny Laroche-Traineau, Johan Garaude, Sébastien Marais, Marie-Josée Jacobin-Valat, Edouard Gerbaud, Gisèle Clofent-Sanchez and Florence Ottones

Int. J. Mol. Sci. 2024, 25(18), 10146; https://doi.org/10.3390/ijms251810146 - 21 Sep 2024

Viewed by 867

Abstract

Different types of macrophages (Mφ) are involved in atherogenesis, including inflammatory Mφ and foamy Mφ (FM). Our previous study demonstrated that two-photon excited fluorescence (TPEF) imaging of NADH and FAD autofluorescence (AF) could distinguish experimental models that mimic the different atherosclerotic Mφ types. The present study assessed whether optical differences correlated with phenotypic and functional differences, potentially guiding diagnostic and therapeutic strategies. Phenotypic differences were investigated using three-dimensional principal component analysis and multi-color flow cytometry. Functional analyses focused on cytokine production, metabolic profiles, and cellular oxidative stress, in LDL dose-dependent assays, to understand the origin of AF in the FAD spectrum and assess FM ability to transition toward an immunoregulatory phenotype and function. Phenotypic studies revealed that FM models generated with acetylated LDL (Mac) were closer to immunoregulatory Mφ, while those generated with oxidized LDL (Mox) more closely resembled inflammatory Mφ. The metabolic analysis confirmed that inflammatory Mφ primarily used glycolysis, while immunoregulatory Mφ mainly depended on mitochondrial respiration. FM models employed both pathways; however, FM models generated with high doses of modified LDL showed reduced mitochondrial respiration, particularly Mox FM. Thus, the high AF in the FAD spectrum in Mox was not linked to increased mitochondrial respiration, but correlated with the dose of oxidized LDL, leading to increased production of reactive oxygen species (ROS) and lysosomal ceroid accumulation. High FAD-like AF, ROS, and ceroid accumulation were reduced by incubation with α-tocopherol. The cytokine profiles supported the phenotypic analysis, indicating that Mox FM exhibited greater inflammatory activity than Mac FM, although both could be redirected toward immunoregulatory functions, albeit to different degrees. In conclusion, in the context of immunoregulatory therapies for atherosclerosis, it is crucial to consider FM, given their prevalence in plaques and our results, as potential targets, regardless of their inflammatory status, alongside non-foamy inflammatory Mφ. Full article

(This article belongs to the Special Issue Atherosclerosis 2.0: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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15 pages, 2629 KiB

Open AccessArticle

Wall Shear Stress (WSS) Analysis in Atherosclerosis in Partial Ligated Apolipoprotein E Knockout Mouse Model through Computational Fluid Dynamics (CFD)

by Minju Cho, Joon Seup Hwang, Kyeong Ryeol Kim and Jun Ki Kim

Int. J. Mol. Sci. 2024, 25(18), 9877; https://doi.org/10.3390/ijms25189877 - 12 Sep 2024

Viewed by 936

Abstract

Atherosclerosis involves an inflammatory response due to plaque formation within the arteries, which can lead to ischemic stroke and heart disease. It is one of the leading causes of death worldwide, with various contributing factors such as hyperlipidemia, hypertension, obesity, diabetes, and smoking. Wall shear stress (WSS) is also known as a contributing factor of the formation of atherosclerotic plaques. Since the causes of atherosclerosis cannot be attributed to a single factor, clearly understanding the mechanisms and causes of its occurrence is crucial for preventing the disease and developing effective treatment strategies. To better understand atherosclerosis and define the correlation between various contributing factors, computational fluid dynamics (CFD) analysis is primarily used. CFD simulates WSS, the frictional force caused by blood flow on the vessel wall with various hemodynamic changes. Using apolipoprotein E knockout (ApoE-KO) mice subjected to partial ligation and a high-fat diet at 1-week, 2-week, and 4-week intervals as an atherosclerosis model, CFD analysis was conducted along with the reconstruction of carotid artery blood flow via magnetic resonance imaging (MRI) and compared to the inflammatory factors and pathological staining. In this experiment, a comparative analysis of the effects of high WSS and low WSS was conducted by comparing the standard deviation of time-averaged wall shear stress (TAWSS) at each point within the vessel wall. As a novel approach, the standard deviation of TAWSS within the vessel was analyzed with the staining results and pathological features. Since the onset of atherosclerosis cannot be explained by a single factor, the aim was to find the correlation between the thickness of atherosclerotic plaques and inflammatory factors through standard deviation analysis. As a result, the gap between low WSS and high WSS widened as the interval between weeks in the atherosclerosis mouse model increased. This finding not only linked the occurrence of atherosclerosis to WSS differences but also provided a connection to the causes of vulnerable plaques. Full article

(This article belongs to the Special Issue Atherosclerosis 2.0: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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14 pages, 1432 KiB

Open AccessArticle

Osteoprotegerin Is Essential for the Development of Endothelial Dysfunction Induced by Angiotensin II in Mice

by Mieczysław Dutka, Wojciech Garczorz, Agnieszka Kosowska, Elzbieta Buczek, Piotr Godek, Wojciech Wojakowski and Tomasz Francuz

Int. J. Mol. Sci. 2024, 25(12), 6434; https://doi.org/10.3390/ijms25126434 - 11 Jun 2024

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Abstract

Opinions on the effects of osteoprotegerin (OPG) have evolved over the years from a protein protecting the vasculature from calcification to a cardiovascular risk factor contributing to inflammation within the vascular wall. Nowadays, the link between OPG and angiotensin II (Ang II) appears to be particularly important. In this study, the endothelial function was investigated in OPG-knockout mice (B6.129.S4-OPG, OPG⁻) and wild-type (C57BL/6J, OPG⁺) mice under basic conditions and after Ang II exposure by assessing the endothelium-dependent diastolic response of aortic rings to acetylcholine in vitro. A further aim of the study was to compare the effect of Ang II on the expression of cytokines in the aortic wall of both groups of mice. Our study shows that rings from OPG⁻ mice had their normal endothelial function preserved after incubation with Ang II, whereas those from OPG⁺ mice showed significant endothelial dysfunction. We conclude that the absence of OPG, although associated with a pro-inflammatory cytokine profile in the vascular wall, simultaneously protects against Ang II-induced increases in pro-inflammatory cytokines in the murine vascular wall. Our study also demonstrates that the absence of OPG can result in a decrease in the concentration of pro-inflammatory cytokines in the vascular wall after Ang II exposure. The presence of OPG is therefore crucial for the development of Ang II-induced inflammation in the vascular wall and for the development of Ang II-induced endothelial dysfunction. Full article

(This article belongs to the Special Issue Atherosclerosis 2.0: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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21 pages, 621 KiB

Open AccessArticle

Glycoprotein Acetyls Is a Novel Biomarker Predicting Cardiovascular Complications in Rheumatoid Arthritis

by Melody Kasher, Maxim B. Freidin, Frances M. K. Williams, Stacey S. Cherny, Shai Ashkenazi and Gregory Livshits

Int. J. Mol. Sci. 2024, 25(11), 5981; https://doi.org/10.3390/ijms25115981 - 30 May 2024

Viewed by 1308

Abstract

The relationship between rheumatoid arthritis (RA) and early onset atherosclerosis is well depicted, each with an important inflammatory component. Glycoprotein acetyls (GlycA), a novel biomarker of inflammation, may play a role in the manifestation of these two inflammatory conditions. The present study examined a potential mediating role of GlycA within the RA–atherosclerosis relationship to determine whether it accounts for the excess risk of cardiovascular disease over that posed by lipid risk factors. The UK Biobank dataset was acquired to establish associations among RA, atherosclerosis, GlycA, and major lipid factors: total cholesterol (TC), high- and low-density lipoprotein (HDL, LDL) cholesterol, and triglycerides (TGs). Genome-wide association study summary statistics were collected from various resources to perform genetic analyses. Causality among variables was tested using Mendelian Randomization (MR) analysis. Genes of interest were identified using colocalization analysis and gene enrichment analysis. MR results appeared to indicate that the genetic relationship between GlycA and RA and also between RA and atherosclerosis was explained by horizontal pleiotropy (p-value = 0.001 and <0.001, respectively), while GlycA may causally predict atherosclerosis (p-value = 0.017). Colocalization analysis revealed several functionally relevant genes shared between GlycA and all the variables assessed. Two loci were apparent in all relationships tested and included the HLA region as well as SLC22A1. GlycA appears to mediate the RA–atherosclerosis relationship through several possible pathways. GlycA, although pleiotropically related to RA, appears to causally predict atherosclerosis. Thus, GlycA is suggested as a significant factor in the etiology of atherosclerosis development in RA. Full article

(This article belongs to the Special Issue Atherosclerosis 2.0: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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28 pages, 9231 KiB

Open AccessArticle

Multi-Omics Profiling of Human Endothelial Cells from the Coronary Artery and Internal Thoracic Artery Reveals Molecular but Not Functional Heterogeneity

by Alexey Frolov, Arseniy Lobov, Marsel Kabilov, Bozhana Zainullina, Alexey Tupikin, Daria Shishkova, Victoria Markova, Anna Sinitskaya, Evgeny Grigoriev, Yulia Markova and Anton Kutikhin

Int. J. Mol. Sci. 2023, 24(19), 15032; https://doi.org/10.3390/ijms241915032 - 9 Oct 2023

Cited by 4 | Viewed by 2154

Abstract

Major adverse cardiovascular events occurring upon coronary artery bypass graft surgery are typically accompanied by endothelial dysfunction. Total arterial revascularisation, which employs both left and right internal thoracic arteries instead of the saphenous vein to create a bypass, is associated with better mid- and long-term outcomes. We suggested that molecular profiles of human coronary artery endothelial cells (HCAECs) and human internal mammary artery endothelial cells (HITAECs) are coherent in terms of transcriptomic and proteomic signatures, which were then investigated by RNA sequencing and ultra-high performance liquid chromatography-mass spectrometry, respectively. Both HCAECs and HITAECs overexpressed molecules responsible for the synthesis of extracellular matrix (ECM) components, basement membrane assembly, cell-ECM adhesion, organisation of intercellular junctions, and secretion of extracellular vesicles. HCAECs were characterised by higher enrichment with molecular signatures of basement membrane construction, collagen biosynthesis and folding, and formation of intercellular junctions, whilst HITAECs were notable for augmented pro-inflammatory signaling, intensive synthesis of proteins and nitrogen compounds, and enhanced ribosome biogenesis. Despite HCAECs and HITAECs showing a certain degree of molecular heterogeneity, no specific markers at the protein level have been identified. Coherence of differentially expressed molecular categories in HCAECs and HITAECs suggests synergistic interactions between these ECs in a bypass surgery scenario. Full article

(This article belongs to the Special Issue Atherosclerosis 2.0: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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Review

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19 pages, 665 KiB

Open AccessReview

Insights from Murine Studies on the Site Specificity of Atherosclerosis

by Godfrey S. Getz and Catherine A. Reardon

Int. J. Mol. Sci. 2024, 25(12), 6375; https://doi.org/10.3390/ijms25126375 - 9 Jun 2024

Cited by 1 | Viewed by 895

Abstract

Atherosclerosis is an inflammatory reaction that develops at specific regions within the artery wall and at specific sites of the arterial tree over a varying time frame in response to a variety of risk factors. The mechanisms that account for the interaction of systemic factors and atherosclerosis-susceptible regions of the arterial tree to mediate this site-specific development of atherosclerosis are not clear. The dynamics of blood flow has a major influence on where in the arterial tree atherosclerosis develops, priming the site for interactions with atherosclerotic risk factors and inducing cellular and molecular participants in atherogenesis. But how this accounts for lesion development at various locations along the vascular tree across differing time frames still requires additional study. Currently, murine models are favored for the experimental study of atherogenesis and provide the most insight into the mechanisms that may contribute to the development of atherosclerosis. Based largely on these studies, in this review, we discuss the role of hemodynamic shear stress, SR-B1, and other factors that may contribute to the site-specific development of atherosclerosis. Full article

(This article belongs to the Special Issue Atherosclerosis 2.0: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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16 pages, 1460 KiB

Open AccessReview

Coronary Plaque Erosion: Epidemiology, Diagnosis, and Treatment

by Panagiotis Theofilis, Panayotis K. Vlachakis, Aggelos Papanikolaou, Paschalis Karakasis, Evangelos Oikonomou, Konstantinos Tsioufis and Dimitris Tousoulis

Int. J. Mol. Sci. 2024, 25(11), 5786; https://doi.org/10.3390/ijms25115786 - 26 May 2024

Cited by 2 | Viewed by 1698

Abstract

Plaque erosion (PE), a distinct etiology of acute coronary syndromes (ACSs), is often overshadowed by plaque ruptures (PRs). Concerning its epidemiology, PE has garnered increasing recognition, with recent studies revealing its prevalence to be approximately 40% among ACS patients, challenging earlier assumptions based on autopsy data. Notably, PE exhibits distinct epidemiological features, preferentially affecting younger demographics, particularly women, and often manifesting as a non-ST-segment elevation myocardial infarction. There are seasonal variations, with PE events being less common in winter, potentially linked to physiological changes and cholesterol solidification, while peaking in summer, warranting further investigation. Moving to molecular mechanisms, PE presents a unique profile characterized by a lesser degree of inflammation compared to PR, with endothelial shear stress emerging as a plausible molecular mechanism. Neutrophil activation, toll-like receptor-2 pathways, and hyaluronidase 2 expression are among the factors implicated in PE pathophysiology, underscoring its multifactorial nature. Advancements in intravascular imaging diagnostics, particularly optical coherence tomography and near-infrared spectroscopy coupled with intravascular ultrasound, offer unprecedented insights into plaque composition and morphology. Artificial intelligence algorithms show promise in enhancing diagnostic accuracy and streamlining image interpretation, augmenting clinician decision-making. Therapeutically, the management of PE evolves, with studies exploring less invasive approaches such as antithrombotic therapy without stenting, particularly in cases identified early through intravascular imaging. Additionally, the potential role of drug-coated balloons in reducing thrombus burden and minimizing future major adverse cardiovascular events warrants further investigation. Looking ahead, the integration of advanced imaging modalities, biomarkers, and artificial intelligence promises to revolutionize the diagnosis and treatment of coronary PE, ushering in a new era of personalized and precise cardiovascular care. Full article

(This article belongs to the Special Issue Atherosclerosis 2.0: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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26 pages, 2576 KiB

Open AccessReview

The Role of Cilostazol, a Phosphodiesterase-3 Inhibitor, in the Development of Atherosclerosis and Vascular Biology: A Review with Meta-Analysis

by Minji Sohn and Soo Lim

Int. J. Mol. Sci. 2024, 25(5), 2593; https://doi.org/10.3390/ijms25052593 - 23 Feb 2024

Cited by 5 | Viewed by 3896

Abstract

Atherosclerotic cardiovascular disease (ASCVD) stands as the leading global cause of mortality. Addressing this vital and pervasive condition requires a multifaceted approach, in which antiplatelet intervention plays a pivotal role, together with antihypertensive, antidiabetic, and lipid-lowering therapies. Among the antiplatelet agents available currently, cilostazol, a phosphodiesterase-3 inhibitor, offers a spectrum of pharmacological effects. These encompass vasodilation, the impediment of platelet activation and aggregation, thrombosis inhibition, limb blood flow augmentation, lipid profile enhancement through triglyceride reduction and high-density lipoprotein cholesterol elevation, and the suppression of vascular smooth muscle cell proliferation. However, the role of cilostazol has not been clearly documented in many guidelines for ASCVD. We comprehensively reviewed the cardiovascular effects of cilostazol within randomized clinical trials that compared it to control or active agents and involved individuals with previous coronary artery disease or stroke, as well as those with no previous history of such conditions. Our approach demonstrated that the administration of cilostazol effectively reduced adverse cardiovascular events, although there was less evidence regarding its impact on myocardial infarction. Most studies have consistently reported its favorable effects in reducing intermittent claudication and enhancing ambulatory capacity in patients with peripheral arterial disease. Furthermore, cilostazol has shown promise in mitigating restenosis following coronary stent implantation in patients with acute coronary syndrome. While research from more diverse regions is still needed, our findings shed light on the broader implications of cilostazol in the context of atherosclerosis and vascular biology, particularly for individuals at high risk of ASCVD. Full article

(This article belongs to the Special Issue Atherosclerosis 2.0: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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