MicroRNA-29 in Aortic Dilation: Implications for Aneurysm Formation

Abstract

Rationale: Aging represents a major risk factor for coronary artery disease and aortic aneurysm formation. MicroRNAs (miRs) have emerged as key regulators of biological processes, but their role in age-associated vascular pathologies is unknown.Objective: We aim to identify miRs in the vasculature that are regulated by age and play a role in age-induced vascular pathologies. Methods and Results:Expression profiling of aortic tissue of young versus old mice identified several ageassociated miRs. Among the significantly regulated miRs, the increased expression of miR-29 family members was associated with a profound downregulation of numerous extracellular matrix (ECM) components in aortas of aged mice, suggesting that this miR family contributes to ECM loss, thereby sensitizing the aorta for aneurysm formation. Indeed, miR-29 expression was significantly induced in 2 experimental models for aortic dilation: angiotensin II-treated aged mice and genetically induced aneurysms in Fibulin-4 R/R mice. More importantly, miR-29b levels were profoundly increased in biopsies of human thoracic aneurysms, obtained from patients with either bicuspid (n‫)97؍‬ or tricuspid aortic valves (n‫.)03؍‬ Finally, LNA-modified antisense oligonucleotidemediated silencing of miR-29 induced ECM expression and inhibited angiotensin II-induced dilation of the aorta in mice. Key Words: microRNA Ⅲ aging Ⅲ aneurysm A ge is one of the major risk factors for cardiovascular diseases. With increasing life expectancy, the prevalence of aging-associated cardiovascular diseases will even increase in the near future. 1 One particular age-associated disease is abdominal aortic aneurysm formation, which affects approximately 9% of elderly men and has a high mortality rate. 2 On the other hand, aneurysms in the ascending part of the thoracic aorta are less age-associated and are often the result of genetic defects involving extracellular matrix (ECM) components. 3 On a mechanistic level, analysis of human pathological sections revealed that aneurysm formation and rupture are characterized by thinning of the vascular wall and blood vessel dilation. 4 Decreased formation and/or increased degradation of ECM are believed to be the key pathophysiological processes leading to vascular wall thinning. 5,6 Original received July 19, 2011; revision received August 28, 2011; accepted August 30, 2011. In July 2011, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.5 days. MicroRNAs (miRs) have recently emerged as key regulators of several (patho-) physiological processes. MiRs are short noncoding RNAs that regulate protein expression by inducing degradation of the targeted mRNA or by blocking protein translation. Whereas various studies showed that specific miRs control vessel growth and cardiac function, 7 the involvement of miRs in aortic wall pathologies are less well known. Conclusion:

MicroRNA‑24 inhibits the proliferation and migration of endothelial cells in patients with atherosclerosis by targeting importin‑α3 and regulating inflammatory responses

“…In addition, reduced miR-126 and increased miR-125b expression results in increased endothelial inflammatory response protein secretion (36). miR-29 affects the production of collagen and elastin, and has important roles in maintaining arterial structural integrity (37). The results of the present study indicate that overexpression of miR-24 inhibits the proliferation and migration of endothelial cells.…”

Emerging Role of MicroRNAs in Cardiovascular Diseases

“…[32][33][34][35] In fact, a significant regulation of the miR-29 family has been observed in old vs. young mice. 36 Very interestingly, the same miRs are mod- Several miRs are expressed in biologically relevant levels in most cells and tissues of the cardiovascular system. 5 In addition, miRs are seemingly released into the bloodstream, offering the opportunity to monitor the biological status of the cardiovascular system through the measurement of the expression pattern of specific miRs in the blood.…”

“…33, 34 The association becomes much more interesting as it is known that the miR-29 family is expressed in high amounts in the aorta of aged mice, where it induces a decrease in elastin and collagen, with a general reduction of extracellular matrix, which is responsible for a higher susceptibility to aneurysm formation. 36 Interestingly, recent studies showed that the inhibition of the miR-29 family can be helpful in enhancing the structural stability of the vessel wall. In fact, the selective inhibition of miR-29 with a specific antagonist induced an increase in the expression of matrix proteins, which prevented aneurysm formation both in angiotensin II-induced aneurysm and in genetic models of aneurysm formation.…”

“…In fact, the selective inhibition of miR-29 with a specific antagonist induced an increase in the expression of matrix proteins, which prevented aneurysm formation both in angiotensin II-induced aneurysm and in genetic models of aneurysm formation. [35][36][37][38][39][40] Despite being modulated in senescent cells and in aged mice, the miR-34 seems to affect age-related disorders in a further way. In fact, its overexpression induces senescence in pro-angiogenic cultured endothelial progenitor cells, 41 and promotes cell death in bone marrow-derived pro-angiogenic cells.…”

Using Proteomics to Understand Abdominal Aortic Aneurysms: Where Are We?

“…Indeed, some recent studies clearly demonstrated the roles of miRNAs in the development of AAA [41][42][43][44]. Zampetaki et al [45] examined miR-195, a member of the miR-15 family.…”