RATIONALE: Yes-associated protein (YAP), the terminal effector of the Hippo 
signaling pathway, is crucial for regulating embryonic cardiomyocyte 
proliferation.
OBJECTIVE: We hypothesized that YAP activation after myocardial infarction (MI) 
would preserve cardiac function and improve survival.
METHODS AND RESULTS: We used a cardiac-specific, inducible expression system to 
activate YAP in adult mouse heart. Activation of YAP in adult heart promoted 
cardiomyocyte proliferation and did not deleteriously affect heart function. 
Furthermore, YAP activation after MI preserved heart function and reduced 
infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery 
vector, we expressed human YAP (hYAP) in the adult murine myocardium immediately 
after MI. We found that AAV9:hYAP significantly improved cardiac function and 
mouse survival. AAV9:hYAP did not exert its salutary effects by reducing 
cardiomyocyte apoptosis. Rather, AAV9:hYAP stimulated adult cardiomyocyte 
proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated 
expression of cell cycle genes and promoted a less mature cardiac gene 
expression signature.
CONCLUSIONS: Cardiac-specific YAP activation after MI mitigated myocardial 
injury, improved cardiac function, and enhanced survival. These findings suggest 
that therapeutic activation of YAP or its downstream targets, potentially 
through AAV-mediated gene therapy, may be a strategy to improve outcome after 
MI.