Abstract 16460: Mir-206, Distinct From MiR-1, Mediates YAP-Induced Cardiac Hypertrophy and Survival
The Drosophila Hippo regulates apoptosis and proliferation through suppression of Yorkie, a transcription factor co-factor, and the microRNA, bantam. YAP, a homologue of Yorkie, stimulates hypertrophy and inhibits apoptosis in cardiomyocytes (CMs). We found that miR-206 is significantly upregulated by YAP in CMs. miR-206 and miR-1 are homologous muscle-specific microRNAs, constituting the miRNA-1/206 family. YAP-induced upregulation of miR-206 was confirmed with Northern blot (+1.4 fold, p<0.05), qRT-PCR (+1.6 fold, p<0.05), and a reporter gene containing the miR-206 enhancer (+1.9 fold, p<0.01). Upregulation of miR-1 or miR-1 enhancer by YAP was not significant. miR-206 induced hypertrophy, as evidenced by increases in cell size (CS, +1.2 fold, p<0.05), total protein content (PC, +1.1 fold, p<0.05), and mRNA expression of atrial natriuretic factor (ANF) (+1.8 fold, p<0.05) in CMs. However, miR-1 inhibited hypertrophy, as evidenced by decreases in PC (-10%, p<0.05). Downregulation of miR-206 attenuated YAP-induced hypertrophy, as evidenced by decreases in CS (-15%, p<0.05), PC (-10%, p<0.05) and ANF luciferase activity (-64.4%, p<0.05). However, downregulation of miR-1 tended to exaggerate YAP-induced hypertrophy. We generated transgenic mice (Tg) with cardiac specific overexpression of miR-206 (Tg-miR-206). Tg-miR-206 exhibited cardiac hypertrophy at baseline, as evidenced by increases in left ventricular weight/body weight (+1.3 fold, p<0.05), CM cross sectional area (+1.3 fold, p<0.01), and mRNA expression of ANF (+2.9 fold, p<0.01). Both YAP and miR-206 were downregulated after myocardial infarction (MI) in the heart in vivo. In contrast with miR-1, which induces cell death, overexpression of either YAP or miR-206 increased survival and downregulation of miR-206 decreased survival of CMs in vitro (+1.4 and +1.2 fold, -38%, p<0.05). We also generated Tg with cardiac specific overexpression of anti-sense miR-206. These mice exhibited a larger MI in response to ischemia/reperfusion (I/R) than control mice, suggesting that endogenous miR-206 is protective during I/R. In summary, YAP upregulates miR-206, which in turn mediates hypertrophy and survival in CMs. miR-206, distinct from miR-1, mimics the function of Drosophila bantam.
- © 2011 by American Heart Association, Inc.