The Role of Epigenetic Modifications in Abdominal Aortic Aneurysm Pathogenesis

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity and mortality in the setting of acute rupture. Recently, advances in surgical and endovascular repair of AAA have been achieved; however, pharmaceutical therapies to prevent AAA expansion and rupture remain lacking. This highlights an ongoing need to improve the understanding the pathological mechanisms that initiate formation, maintain growth, and promote rupture of AAA. Over the past decade, epigenetic modifications, such as DNA methylation, posttranslational histone modifications, and non-coding RNA, have emerged as important regulators of cellular function. Accumulating studies reveal the importance of epigenetic enzymes in the dynamic regulation of key signaling pathways that alter cellular phenotypes and have emerged as major intracellular players in a wide range of biological processes. In this review, we discuss the roles and implications of epigenetic modifications in AAA animal models and their relevance to human AAA pathology.

Large Vessel Cell Heterogeneity and Plasticity: Focus in Aortic Aneurysms

“…Cell phenotypes in aortic aneurysms can also be affected by epigenetic modifications, that is, DNA methylation, histone modifications, and noncoding RNA (for detailed review, see Mangum et al 43 and Boileau et al 44 ). Although, modulation of immune cell, SMC and EC gene expression and cellular function, promoted by epigenetic regulators and with potential consequences on TAA/AAA progression, have been extensively studied in cells and AAA indicates abdominal aortic aneurysm; ACTA2, actin, aortic smooth muscle; ADIPOQ, adiponectin; BAV, bicuspid aortic valve; EC, endothelial cell; F, female; FBN1, fibrillin-1; IHC, immunohistochemistry; iNOS, nitric oxide synthase, inducible; LAMP2, lysosome-associated membrane glycoprotein 2; LOX, lysyl oxidase; M, male; MMP, matrix metalloproteinases; ModSMC, modulated SMCs; MSC, mesenchymal stem cell; MYH11, myosin-11; NA, not applicable; OPN or SPP1, osteopontin; RT-qPCR, quantitative reverse transcription polymerase chain reaction; scRNA-seq, single-cell RNA sequencing; SMC, smooth muscle cells; TAA, thoracic aortic aneurysm; TAV, Tricuspid aortic valve; and TGF-β, transforming growth factor-β.…”

“…Cell phenotypes in aortic aneurysms can also be affected by epigenetic modifications, that is, DNA methylation, histone modifications, and noncoding RNA (for detailed review, see Mangum et al 43 and Boileau et al 44 ). Although, modulation of immune cell, SMC and EC gene expression and cellular function, promoted by epigenetic regulators and with potential consequences on TAA/AAA progression, have been extensively studied in cells and murine aneurysm models, limited knowledge exists from patients.…”

N6-methyladenosine-associated genetic variants in NECTIN2 and HPCAL1 are risk factors for abdominal aortic aneurysm

“… 1 , 2 Furthermore, extensive research has highlighted the significant role of genetic factors in the onset and progression of AAA. 3 , 4 Despite numerous candidate gene association studies conducted, most of them have not been replicated in independent cohorts, indicating the need for further investigation and validation. 5 …”

Tributyrin Intake Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm in LDLR-/- Mice

“…The role of epigenetic modification in several kinds of cells within pathogenic aortic aneurysm formation has been demonstrated. For instance, epigenetic regulation of VSMCs has been shown to play key roles in a variety of vascular diseases, including atherosclerosis, hypertension, restenosis after angioplasty, and the development and progression of AAA [18][19][20]. Treatment with histone deacetylase (HDAC) class I or class IIa inhibitors reduced AAA incidence, decreased macrophage inflammation, and reduced proinflammatory mediators in a murine model [21].…”