Pathogenetic Potential of the Epigenetic Status of Genes of Mendelian Forms of Thoracic Aortic Aneurysms

Abstract

Rare pathogenic variants in genes whose protein products form the structure of the extracellular matrix, regulate smooth muscle cell function, or belong to the TGFβ/SMAD signaling pathway are detected in 20–30% of thoracic aortic aneurysm (TAA) cases. In addition to the structural changes, epigenetic events associated with these genes may influence the risk of aortic aneurysm. This review summarizes the published study results on the functional significance of epigenetic modifications in the genes of Mendelian forms of TAA. Most TAA genes are characterized by overlapping localization with genomic noncoding regulatory elements (including genes of microRNAs, long noncoding RNAs, etc.). These genomic regions have not been practically studied in patients with aortic aneurysm, but a number of noncoding RNAs (ACTA2-AS1, TGFB2-AS1, PRKG1-AS1) have been shown to be involved in the regulation of processes pathogenetically significant for aortic aneurysm (proliferation, apoptosis, autophagy, inflammation, endothelial dysfunction) and metabolic pathways (TGFβ/SMAD, Wnt/β-catenin). In the regions of TAA genes, the changes in DNA methylation are also recorded both in the presence of risk factors (structural features of the aorta, blood flow patterns) and in the development of aortic aneurysm. Various epigenetic events may also exert the pathogenic effects of aortic aneurysm-associated genetic variants localized in TAA genes. Thus, despite the fact that the long noncoding RNA and microRNA genes located in the TAA gene region and various epigenetic events (including histone modifications and DNA methylation) have not been sufficiently studied in this aortopathy, the information provided in scientific publications allows us to consider these epigenetic markers as promising regulators of certain pathogenetic processes in the development of an aortic aneurysm.