Epigenetics in Ascending Thoracic Aortic Aneurysm and Dissection

Abstract

Thoracic aortic aneurysm (TAA) is an asymptomatic and progressive dilatation of the thoracic aorta. Ascending aortic dissection (AAD) is an acute intraparietal tear, occurring or not on a pre-existing dilatation. AAD is a condition associated with a poor prognosis and a high mortality rate. TAA and AAD share common etiology as monogenic diseases linked to transforming growth factor β signaling pathway, extracellular matrix defect, or smooth muscle cell protein mutations. They feature a complex pathogenesis including loss of smooth muscle cells, altered phenotype, and extracellular matrix degradation in aortic media layer. A better knowledge of the mechanisms responsible for TAA progression and AAD occurrence is needed to improve healthcare, nowadays mainly consisting of aortic open surgery or endovascular replacement. Recent breakthrough discoveries allowed a deeper characterization of the mechanisms of gene regulation. Since alteration in gene expression has been linked to TAA and AAD, it is conceivable that a better knowledge of the causes of this alteration may lead to novel theranostic approaches. In this review article, the authors will focus on epigenetic regulation of gene expression, including the role of histone methylation and acetylation, deoxyribonucleic acid methylation, and noncoding ribonucleic acids in the pathogenesis of TAA and AAD. They will provide a translational perspective, presenting recent data that motivate the evaluation of the potential of epigenetics to diagnose TAA and prevent AAD.

Fig. 1

Overview of epigenetic mechanisms. Epigenetic modifications include (1) modifications of DNA-associated histone proteins, (2) DNA methylation, and (3) noncoding RNAs. Abbreviations: DNA, deoxyribonucleic acid; LncRNA, long noncoding RNA; mRNA, messenger RNA; miRNA, microRNA; RNA, ribonucleic acid.

Fig. 2

Schematic representation of the differential biology between chronic dilation of the aorta (aneurysm) and acute intraparietal rupture (dissection). The progressive development of chromatin remodeling in aortic smooth muscle cells (aSMC) in response to small dilation or matrix proteolytic injury could reduce the risk of acute rupture. Abbreviations: PN-1, protease nexin-1, PAI-1, plasminogen activator inhibitor-1.

Fig. 3

Involvement of microribonucleic acids (miRNAs) and long noncoding RNAs (lncRNAs) in aortic smooth muscle cell (aSMC) phenotypic switch.