miR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival
Rationale: In Drosophila, the Hippo signaling pathway negatively regulates organ size by suppressing cell proliferation and survival through the inhibition of Yorkie, a transcriptional co-factor. Yes-associated protein (YAP), the mammalian homolog of Yorkie, promotes cardiomyocyte growth and survival in postnatal hearts. However, the underlying mechanism responsible for the beneficial effect of YAP in cardiomyocytes remains unclear.
Objective: We investigated whether miR-206, a microRNA known to promote hypertrophy in skeletal muscle, mediates the effect of YAP upon promotion of survival and hypertrophy in cardiomyocytes.
Methods and Results: Microarray analysis indicated that YAP increased miR-206 expression in cardiomyocytes. Increased miR-206 expression induced cardiac hypertrophy and inhibited cell death in cultured cardiomyocytes, similar to that of YAP. Down regulation of endogenous miR-206 in cardiomyocytes attenuated YAP-induced cardiac hypertrophy and survival, suggesting that miR-206 plays a critical role in mediating YAP function. Cardiac-specific overexpression of miR-206 in mice induced hypertrophy and protected the heart from ischemia/reperfusion (I/R) injury, whereas suppression of miR-206 exacerbated I/R injury and prevented pressure overload-induced cardiac hypertrophy. miR-206 negatively regulates FoxP1 expression in cardiomyocytes and overexpression of FoxP1 attenuated miR-206-induced cardiac hypertrophy and survival, suggesting that FoxP1 is a functional target of miR-206.
Conclusions: YAP increases the abundance of miR-206, which in turn plays an essential role in mediating hypertrophy and survival by silencing FoxP1 in cardiomyocytes.
- Received April 6, 2015.
- Revision received August 28, 2015.
- Accepted September 2, 2015.