Pathophysiology of Atherosclerotic Plaque Development-Contemporary Experience and New Directions in Research

Abstract

Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, many molecular mechanisms affecting this process are still to be revealed. This minireview aims to describe the current directions in research on atherogenesis and to summarize selected studies published in recent years-in particular, studies on novel cellular pathways, epigenetic regulations, the influence of hemodynamic parameters, as well as tissue and microorganism (microbiome) influence on atherosclerotic plaque development. Finally, some new and interesting ideas are proposed (immune cellular heterogeneity, non-coding RNAs, and immunometabolism) which will hopefully bring new discoveries in this area of investigation.

Keywords: atherogenesis; atherosclerotic plaque; epigenetics; future perspectives; genetics; inflammation; investigations; macrophage; non coding RNA.

Figure 1

The essential stages of the process of atherosclerotic plaque initiation and progression. ROS—reactive oxygen species, ECM—extracellular matrix, VSMC—vascular smooth muscle cell, CD36—cluster of differentiation 36, TLR4/TLR6—Toll-like receptor 4/6, NLRP3—Nod-like receptor protein 3, NF-κB—nuclear factor kappa B, MMPs—matrix metalloproteinases.

Figure 2

Methodological approaches in studies on atherosclerotic plaque development and progression: *—example studies; 1—assessed by computed tomography coronary angiography (CTCA), 2—assessed by intravascular ultrasound (IVUS) or positron emission tomography (PET); 3—for instance: chronic vs. acute coronary syndrome patients; 4—chromatin state assessment (ChIP—chromatin immunoprecipitation); 5—promoter and transcription factor assessment; 6—by microarray, next-generation sequencing (NGS) and quantitative real-time polymerase chain reaction (qRT-PCR); 7—systemic studies, i.e., genomic (genome-wide association study—GWAS), proteomic, transcriptomic, metabolomic; 8—hematoxylin-eosin staining, immunohistochemistry; 9—major adverse cardiovascular events (MACE), i.e., myocardial infarction, stroke, need for urgent revascularization. Other abbreviations: siRNA—small interfering RNA, HUVEC—human umbilical vein endothelial cell, miRNA—microRNA, CMR—cardiac magnetic resonance imaging, ApoE—apolipoprotein E, LDLR—low-density lipoprotein receptor, VO₂ max—maximum rate of oxygen consumption.

Figure 3

Insight into the perspectives of future research on atherosclerotic plaque—three main proposed directions of exploration: (A)—heterogeneity of immune cells, (B)—non-coding RNA influence, (C)—immunometabolism.