Genetics of Arterial-Wall-Specific Mechanisms in Atherosclerosis: Focus on Mitochondrial Mutations
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GENETICS AND GENOMICS (A.J. MARIAN, SECTION EDITOR)
Genetics of Arterial-Wall-Specific Mechanisms in Atherosclerosis: Focus on Mitochondrial Mutations Alexander N. Orekhov 1,2 & Ekaterina A. Ivanova 3 & Alexander M. Markin 2 & Nikita G. Nikiforov 4,5 & Igor A. Sobenin 1,5
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review Mutations in both nuclear and mitochondrial genes are associated with the development of atherosclerotic lesions in arteries and may provide a partial explanation to the focal nature of lesion distribution in the arterial wall. This review is aimed to discuss the genetic aspects of atherogenesis with a special focus on possible pro-atherogenic variants (mutations) of the nuclear and mitochondrial genomes that may be implicated in atherosclerosis development and progression. Recent Findings Mutations in the nuclear genes generally do not cause a phenotype restricted to a specific vascular wall cell and manifest themselves mostly at the organism level. Such mutations can act as important contributors to changes in lipid metabolism and modulate other risk factors of atherosclerosis. By contrast, mitochondrial DNA (mtDNA) mutations occurring locally in the arterial wall cells or in circulating immune cells may play a site-specific role in atherogenesis. The mosaic distribution of heteroplasmic mtDNA mutations in the arterial wall tissue may explain, at least to some extent, the locality and focality of atherosclerotic lesions distribution. Summary The genetic mechanisms of atherogenesis include alterations of both nuclear and mitochondrial genomes. Altered lipid metabolism and inflammatory response of resident arterial wall and circulating immune cells may be related to mtDNA damage and defective mitophagy, which hinders clearance of dysfunctional mitochondria. Mutations of mtDNA can have mosaic distribution and locally affect functionality of endothelial and subendothelial intimal cells in the arterial wall contributing to atherosclerotic lesion development. Keywords Atherosclerosis . Nuclear genome . Mitochondria . Mutations . Inflammation . Mitochondrial DNA
This article is part of the Topical Collection on Genetics and Genomics * Alexander N. Orekhov [email protected] * Ekaterina A. Ivanova [email protected] 1
Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow, Russia 125315
2
Laboratory of Infection Pathology and Molecular Microecology, Institute of Human Morphology, 3 Tsyurupa Street, Moscow, Russia 117418
3
Institute for Atherosclerosis Research, 2-1-207 Osennyaya Street, Moscow, Russia 121609
4
Centre of Collective Usage, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova Street, Moscow, Russia 119334
5
Laboratory of Medical Genetics, Institute of Experimental Cardiology, National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Street, Moscow, Russia 121552
Introduction The risk of atherosclerosis is modulated by both internal (genetic)
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