Cardiac-Specific YAP Activation Improves Cardiac Function and Survival in an Experimental Murine MI Model

Abstract

Rationale Yes-Associated Protein (YAP), the terminal effector of the Hippo signaling pathway, is crucial for regulating embryonic cardiomyocyte (CM) proliferation. Objective We hypothesized that YAP activation after myocardial infarction 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 CM proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after myocardial infarction (MI) preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP 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 CM apoptosis. Rather, AAV9:hYAP stimulated adult CM 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.

View from the heart: cardiac fibroblasts in development, scarring and regeneration

“…A second group (Polizzotti et al, 2015) further showed that administration of neuregulin 1 in neonatal mouse hearts or cardiomyocytes derived from paediatric patients also brings beneficial effects to myocardial function through cardioprotection ( protection from cell death) and proliferation. Nevertheless, none of these experiments has demonstrated a lack of scarring in the adult heart, which is important since the activity of the fibroblast cells also needs to be addressed in order to achieve full regeneration (D'Uva et al, 2015;Lin et al, 2014;Polizzotti et al, 2015;Xin et al, 2013).…”

GATA4 regulates Fgf16 to promote heart repair after injury

“…Therefore, we generated the adeno-associated virus 9:cTNT::Fgf16 virus (AAV9:Fgf16), in which expression of Fgf16 was driven by the cardiomyocytespecific cTNT promoter and the plasmid was packaged into AAV9, a virus that targets cardiomyocytes efficiently and specifically (Lin et al, 2014). We first used AAV9:cTNT::GFP-Cre (AAV9:GFPCre) to evaluate the transduction efficiency and specificity in the Rosa26 RFP/+ reporter mouse.…”

“…AAV9 were packaged in 293T cells with AAV9:Rep/Cap and pAd:deltaF6 ( pHelper) as described previously (Grieger et al, 2006;Lin et al, 2014). AAV9 were then purified and concentrated by gradient centrifugation.…”

Regulation of Myocardial Cell Growth and Death by the Hippo Pathway

“…10 Third, Yap promotes activation of Akt, a serine/threonine kinase that promotes cell survival, through unknown mechanisms stimulating PI3K. 4, 9 The importance of each mechanism may differ depending upon the type of stress.…”