Abstract 200: Cardiomyocyte-specific Deletion Of Rhoa Accelerates Heart Failure But Prevents Cardiac Fibrosis In Response To Pressure-overload

Heart failure is a progressive disease characterized by loss of cardiac contractility, interstitial fibrosis, and chamber remodeling. Though several signaling pathways have been identified, the precise mechanisms involved in regulating pathological cardiac responses remain unclear. The Ras-related small G protein RhoA is an identified mediator of in vivo pathological hypertrophy. However, it also promotes cell survival and is cardioprotective after ischemia/repurfusion injury. Therefore, to determine the molecular mechanisms that underlie these opposing roles for RhoA in the myocardium, we generated mice with cardiomyocyte-specific deletion of RhoA (RhoAfl/fl-αMHC-Cre). As compared to wildtype mice, hearts from RhoAfl/fl-αMHC-Cre mice showed similar functional, structural, and growth parameters, both at baseline and in response to acute transverse aortic constriction (TAC) (2wks), suggesting RhoA plays no major role in either homeostatic or acute stress-induced cardiac conditions. However, after exposure to chronic TAC for 8wks, hearts from RhoAfl/fl-αMHC-Cre mice developed an accelerated dilation, with significant loss of contractile function. Mechanistically, cardiomyocyte-specific loss of RhoA reduced ERK1/2 activation and perturbed agonist-evoked calcium cycling, through aberrant IP3 and DAG signaling, indicating that RhoA mediates its cardioprotective effects through regulation of these pathways. Despite this, and surprisingly, hearts from RhoAfl/fl-αMHC mice also showed significantly decreased TAC-induced cardiac fibrosis, with a demonstrated decrease in transcriptional activation of genes involved in the fibrotic response, including the serum response factor (SRF), as well as the secreted factor BMP7. Taken together, our data reveal an interesting, yet highly complex signaling and regulatory mechanism for RhoA, whereby RhoA signaling is both cardioprotective against development of heart failure in response to chronic stress, but also cardio-deleterious through its capacity to activate pro-fibrotic genes.