Molecular Medicine MicroRNA-29 in Aortic Dilation: Implications for Aneurysm Formation Short Communication

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 age-associated 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 oligonucleotide-mediated silencing of miR-29 induced ECM expression and inhibited angiotensin II-induced dilation of the aorta in mice. Conclusion: In conclusion, miR-29-mediated downregulation of ECM proteins may sensitize the aorta to the formation of aneurysms in advanced age. Inhibition of miR-29 in vivo abrogates aortic dilation in mice, suggesting that miR-29 may represent a novel molecular target to augment matrix synthesis and maintain vascular wall structural integrity. 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 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 …