Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.

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:

Sildenafil reduces hypoxic pulmonary hypertension at rest and during exercise while maintaining gas exchange and systemic blood pressure. To the authors' knowledge, sildenafil is the first drug shown to increase exercise capacity during severe hypoxia both at sea level and at high altitude.