MicroRNAs and Current Concepts on the Pathogenesis of Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm is an important cause of morbidity and mortality in the elderly. Currently, the only way to prevent rupture and death related to abdominal aortic aneurysms is through surgical intervention. Endovascular treatment is associated with less morbidity than conventional treatment. The formation of an aneurysm is a complex multifactorial process, involving destructive remodeling of the connective tissue around the affected segment of the aorta wall. MicroRNAs are small sequences of non-coding RNAs that control diverse cellular functions by promoting degradation or inhibition of translation of specific mRNAs. A profile aberrant expression of miRNAs has been linked to human diseases, including cardiovascular dysfunction.

Fig.1

Schematic representation of the impact of the blood-chronic intraluminal thrombus interface on medial degradation and the adventitial inflammatory, angiogenic and fibrotic responses in human AAA. Abbreviations: ATLO, adventitial tertiary lymphoid organ; and RBCs, red blood cells.

Fig. 2

A general model of miRNA biogenesis and function.

Fig. 3

Pathophysiology of abdominal aortic aneurysms. Schematic diagram illustrating events thought to contribute to the development and progression of abdominal aortic aneurysms. Injury to the aortic wall, either as a consequence of or in association with known risk factors (I), leads to recruitment of leukocytes into the aortic media (II), macrophage (MPh) activation, and production of proinflammatory molecules (III). Macrophages also produce proenzyme forms of matrix metalloproteinases (MMPs) (pro-MMPs) (IV), which are activated in the extracellular space (V). Tissue inhibitors of matrix metalloproteinases (TIMPs) may neutralize MMP activity (VI), but this neutralization appears insufficient to prevent degradation of structural matrix proteins (elastin and interstitial collagens) (VII). Over a period of years, elastin degradation, cyclic strain, and elevated wall tension bring about progressive aortic dilatation (VIII). Collagen degradation further weakens the aortic wall (IX); although medial smooth muscle cells (SMCs) and fibroblasts might promote structural repair, apoptosis, and cellular senescence cause SMC depletion (X), and interstitial collagen appears disorganized (XI). Aneurysm tissues exhibit infiltration by T cells, B lymphocytes, plasma cells, and dendritic cells and local deposition of immunoglobulins, reflecting a cellular and humoral immune response (XII). Understanding the adaptive cellular immune response in abdominal aortic aneurysms may reveal how different T-cell subsets (i.e., helper T cell type 1 [Th1] versus Th2) interact with macro- phages to promote or suppress aneurysmal degeneration, on the basis of the local balance of proinflammatory (XIII) and anti-inflammatory (XIV) molecules. Some cytokines produced within aneurysm tissue, such as interleukin-6 (IL-6) and interferon-γ (IFN-γ), may have dual and opposing functions depending on the specific context (XV). The promotion of miR-29 induces the extracellular matrix degradation and induces the formation of aneurysms (XVI). EDPs, Elastin degradation peptides; PGs, prostaglandins; ROS, reactive oxygen species; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; miR-29, microRNA-29^[70].