Hippo Deficiency Leads to Cardiac Dysfunction with Cardiomyocyte De-differentiation. Mus musculus

The Hippo pathway regulates organ size by modulating cell proliferation and apoptosis. It is activated by myocardial stress and contributes to myocardial injury by promoting cardiomyocyte apoptosis. We investigated the role of the endogenous Hippo pathway in the stressed heart, using cardiac-specific WW45 knockout mice (WW45 cKO). Unexpectedly, chronic suppression of the Hippo pathway exacerbated the progression of heart failure induced by pressure overload (PO), despite reducing apoptosis and promoting cardiomyocyte proliferation. WW45 downregulation induced upregulation of YAP and TEF-1 target genes, including oncostatin M (OSM), and fetal-type genes involved in de-differentiation, as well as myofibrillar disorganization and dysfunction in cardiomyocytes. OSM upregulation further upregulated YAP/TEF-1, thereby potentiating de-differentiation. Suppression of any component of the amplification loop, namely YAP, TEF-1, or OSM, inhibited the effect of Hippo downregulation. Thus, cardiomyocytes under stress risk apoptotic death by activating the Hippo pathway in order to maintain differentiation and contraction against hemodynamic overload. Overall design: Cardiac mRNA profiles of 3-months old control (flox/flox) and cardiac specific WW45 knockout (flox/flox-alpha-MHC-CRE) mice were generated. 1 CT and 1 WW45 cKO mice were at baseline conditions, whereas 1 CT and 1 WW45 cKO were subjected to 4 weeks of transverse aortic constriction (TAC).