MiR-378 Controls Cardiac Hypertrophy by Combined Repression of MAP Kinase Pathway Factors
Background—Several microRNAs (miRs) have been shown to regulate gene expression in the heart and dysregulation of their expression has been linked to cardiac disease. miR-378 is strongly expressed in the mammalian heart, but was so far predominantly studied in cancer, where it regulates cell survival and tumor growth.
Methods and Results—Here, we report tight control of cardiomyocyte (CM) hypertrophy through miR-378. In isolated primary CMs, miR-378 was found both necessary and sufficient to repress CM hypertrophy. Bioinformatic prediction suggested that factors of the MAP kinase pathway are enriched among miR-378 targets. Using mRNA and protein expression analysis along with luciferase assays, we validated four key components of the MAP kinase pathway as targets of miR-378, namely MAPK1 itself, the insulin-like growth factor receptor 1 (IGF1R), growth factor receptor-bound protein 2 (GRB2) and kinase suppressor of ras 1 (KSR1). RNA interference with these targets prevented the pro-hypertrophic effect of anti-miR-378, suggesting their functional relation with miR-378. As miR-378 significantly decreases in cardiac disease, we sought to compensate for its loss through AAV-mediated, CM-targeted expression of miR-378 in an in vivo model of cardiac hypertrophy (pressure overload by thoracic aortic constriction, TAC). Restoration of miR-378 levels significantly attenuated TAC-induced cardiac hypertrophy and improved cardiac function.
Conclusions—Our data identify miR-378 as a regulator of cardiomyocyte hypertrophy, which exerts its activity by suppressing the MAP kinase-signaling pathway on several distinct levels. Restoration of disease-associated loss of miR-378 through CM-targeted AAV-miR-378 may prove as an effective therapeutic strategy in myocardial disease.
- Received December 29, 2012.
- Revision received March 19, 2013.
- Accepted April 5, 2013.