Cellular Mechanisms of Human Atherogenesis: Focus on Chronification of Inflammation and Mitochondrial Mutations

Abstract

Atherosclerosis is one of the most common diseases of the cardiovascular system that leads to the development of life-threatening conditions, such as heart attack and stroke. Arthrosclerosis affects various arteries in the human body, but is especially dangerous in the arteries alimenting heart and brain, aorta, and arteries of the lower limbs. By its pathophysiology, atherosclerosis is an inflammatory disease. During the pathological process, lesions of arterial intima in the form of focal thickening are observed, which form atherosclerotic plaques as the disease progresses further. Given the significance of atherosclerosis for the global health, the search for novel effective therapies is highly prioritized. However, despite the constant progress, our understanding of the mechanisms of atherogenesis is still incomplete. One of the remaining puzzles in atherosclerosis development is the focal distribution of atherosclerotic lesions in the arterial wall. It implies the existence of certain mosaicism within the tissue, with some areas more susceptible to disease development than others, which may prove to be important for novel therapy development. There are many hypotheses explaining this phenomenon, for example, the influence of viruses, and the spread in the endothelium of the vessel multinucleated giant endothelial cells. We suggest the local variations of the mitochondrial genome as a possible explanation of this mosaicism. In this review, we discuss the role of genetic variations in the nuclear and mitochondrial genomes that influence the development of atherosclerosis. Changes in the mitochondrial and nuclear genome have been identified as independent factors for the development of the disease, as well as potential diagnostic markers.

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

“…64 Genetic variations with deletions and mutations in the mtDNA, but also in the nDNA, appear to influence the development of atherosclerosis and have been recognized as independent factors for disease emergence and may constitute potential diagnostic markers. 65,66 Interestingly, local differences of the mitochondrial genome have been suggested as a possible explanation of the mosaicism noted within the arterial tissue that leads to the focal localization of atherosclerotic lesions in the arterial wall, whereby some areas are more susceptible to development of atherosclerosis than others; these variations may turn out to be important for development of novel therapies. 65 A meta-analysis of 15 randomized controlled trials (RCTs) enrolling 5680 ST-elevation myocardial infarction (STEMI) patients having primary percutaneous coronary intervention (PCI) and comparatively evaluating drugs aimed at mitochondrial function versus placebo, indicated that drugs targeting a particular mitochondrial component/pathway did not lead to a significant decrease of CV and all-cause mortality (OR, 0.90 and OR, 0.92, respectively).…”

“…Importantly, recent studies have indicated a number of mtDNA mutations, with the heteroplasmy level (proportion of normal and mutant mtDNAs present within the cell) linked to atherosclerosis, either positively or negatively, including early subclinical atherosclerotic disease; the mutations were detected in the genes that encode for the mitochondrial ribosomes, electron transport chain enzymes, and tRNA 64 . Genetic variations with deletions and mutations in the mtDNA, but also in the nDNA, appear to influence the development of atherosclerosis and have been recognized as independent factors for disease emergence and may constitute potential diagnostic markers 65,66 . Interestingly, local differences of the mitochondrial genome have been suggested as a possible explanation of the mosaicism noted within the arterial tissue that leads to the focal localization of atherosclerotic lesions in the arterial wall, whereby some areas are more susceptible to development of atherosclerosis than others; these variations may turn out to be important for development of novel therapies 65 …”

“…Genetic variations with deletions and mutations in the mtDNA, but also in the nDNA, appear to influence the development of atherosclerosis and have been recognized as independent factors for disease emergence and may constitute potential diagnostic markers 65,66 . Interestingly, local differences of the mitochondrial genome have been suggested as a possible explanation of the mosaicism noted within the arterial tissue that leads to the focal localization of atherosclerotic lesions in the arterial wall, whereby some areas are more susceptible to development of atherosclerosis than others; these variations may turn out to be important for development of novel therapies 65 …”

Transcription factor EB regulates cardiovascular homeostasis

“…Although CVDs are heterogeneous in nature, they share some common pathological features, such as atherosclerosis and inflammation [ 37 , 38 ]. Recent studies have revealed that TFEB is critical to maintaining vascular and heart homeostasis ( Fig.…”

STAT3/miR-15a-5p/CX3CL1 Loop Regulates Proliferation and Migration of Vascular Endothelial Cells in Atherosclerosis

“…Although the morbid etiopathogenesis is not entirely decipherable, atherosclerosis is known as a complex and chronic inflammatory disease [1,2]. Endothelial dysfunction occurs at the beginning of atherosclerosis and leads to hardening and thickening of the arterial wall and plaque formation [3].…”