Abstract 13060: Abrogation of miR-195 Improves Function in Aged Heart by Preventing Telomere Shortening and Mitochondrial Dysfunction

Abstract

Background: Recently, we discovered a distinct microRNAs profile in young and old MSCs by microarray which led us to hypothesize that senescence-associated microRNA(miR)-195 plays a critical role in stem cell aging through telomerase reverse transcriptase (tert) deactivation and determined whether direct inhibition of miR-195 in aged myocardium restores juvenile characteristics and improves cardiac function. Methods and Results: To examine the mechanistic participation of miR-195 in cardiac aging and function, we directly injected lentivral miR-195 inhibitor into the normal mice heart through open chest surgery. Interestingly, we observed a significant telomere re-lengthening in myocardium injected with anti-miR-195 as examined by Q-FISH analysis. In addition, heart tissues treated with miR-195 inhibitor markedly restored the expression of anti-aging factors such as Tert, telomeric repeat-binding factor 2 (Trf2) and Sirt1, whereas expression of pro-aging markers including p53 and p16 were reduced. Additionally, we found that mitochondrial activity was significantly improved in miR-195 knocked down heart as examined by cytochrome c oxidase activity assay. To investigate whether abrogation of miR-195 in myocardium improves cardiac function, we performed echocardiography at 4 weeks after injection. The cardiac function was markedly improved in miR-195 knocked down myocardium as evaluated by cardiac performance index, a useful marker for heart failure (0.24±0.05 vs 0.44±0.13, p<0.05, n=6), whereas there was no significant change in systolic function . Furthermore, histological analysis showed that transfection of miR-195 inhibitor markedly reduced fibrosis as well as expression of connective tissue growth factor (CTGF), a fibrogenic master switch, in the aged myocardium as compared to scramble transfected heart. Conclusions: These results demonstrate that abrogation of miR-195 improves cardiac function through restoration of anti-aging factors as well as amelioration of mitochondrial dysfunction. Suppression of miR-195 in aging myocardium is a novel therapeutic strategy for treatment against age-dependent cardiovascular diseases.