Abstract 10698: Direct Inhibition of Senescence-associated Micro195 Revives Aged Myocardium Through Cardiac Telomere Relengthening
Background: Deterioration of cardiac function is aggravated with aging. Since we previously found that senescence-associated microRNA (SA-miR)-195 was increased in aged stem cells and accelerated telomere shortening by telomerase reverse transcriptase (TERT) deactivation, we hypothesized that SA-miR-195 play an important role in cardiac aging and function. In this study, we investigated whether direct inhibition of SA-miR-195 in aged myocardium improves cardiac function.
Methods and Results: Expression of anti-aging factors including Tert and Sirt1 were significantly impaired in the aged heart (20-24 months) as compared to young heart (2-3 months) whereas miR-195 expression was markedly increased in the aged heart. To examine the role of miR-195 in cardiac function, expression of miR-195 in aged myocardium was knocked down by direct injection of lentivirus containing miR-195 inhibitor into the normal mice heart through open chest surgery. Interestingly, we observed a significant telomere re-lengthening in anti-miR-195 injected aged myocardium as examined by quantitative fluorescent in situ hybridization (Q-FISH) analysis. In addition, heart tissues treated with miR-195 inhibitor significantly reactivated the expression of anti-aging factors such as Tert, telomeric repeat-binding factor 2, Sirt1 and FOXO. At 4 weeks after transplantation, echocardiography was performed to assess cardiac function. E/E’ and cardiac performance index which are used as markers of heart failure were markedly improved in miR-195 inhibitor-treated myocardium (11.6±1.4 vs 22.4±2.6 and 0.24±0.05 vs 0.44±0.13, respectively, p<0.05) whereas systolic function such as LVEF and %FS did not show significant changes. Further histological analysis showed that transfection of miR-195 inhibitor markedly reduced fibrosis as well as CTGF expression, a pre-fibrogenic marker, in the aged myocardium as compared to scramble-transfected heart.
Conclusions: Inhibition of SA-miR-195 improves cardiac function through telomere re-lengthening in the aged myocardium. Therefore, suppression of SA-miR-195 in myocardium is a novel therapeutic strategy for treatments against age-related cardiovascular diseases.
- © 2013 by American Heart Association, Inc.