The prevention and treatment of heart disease remain challenging. Rho kinase (also named ROCK) has recently emerged as a potential therapeutic target for various cardiovascular diseases. A long-term goal of our past twenty years of research on ROCK pathophysiology is to define the roles and underlying mechanisms of ROCK-mediated signal pathway in regulating cardiac remodeling. The two members of the ROCK family, ROCK1 and ROCK2, have both shared and distinct cellular functions and can compensate each other in numerous single isoform knockout conditions. The majority of our knowledge on the cellular and molecular function of ROCKs comes from research on proliferative cell types in which ROCKs modulate actin cytoskeleton organization through promoting actomyocin contraction and F-actin stabilization. Cardiomyocytes stand apart from other cell types because they contain both sarcomeric and non-sarcomeric cytoskeleton. There is a gap in our knowledge on how ROCKs regulate sarcomeric and non-sarcomeric F-actin in cardiomyocytes and how these processes contribute to overall heart function. Recently, for the first time to use inducible approach to delete both ROCK isoforms in cardiomyocytes, we have discovered that although ROCKs are not required for maintaining sarcomeric cytoskeleton in adult hearts, they do participate in the regulation of non-sarcomeric F-actin organization, inhibit autophagy by promoting mammalian target of rapamycin (mTOR) activity and contribute to age-related cardiac fibrosis. In contrast, the non-sarcomeric F- actin dynamics are able to be maintained with the presence of either isoform in the cardiomyocytes where the other isoform has been deleted; this might be attributed to compensatory over-activation of the remaining isoform in cardiomyocytes having single ROCK isoform deletion. The proposed research aims to further elucidate the pathophysiological roles and downstream pathways of ROCK-mediated actin cytoskeleton changes in cardiomyocytes and fibroblasts under pathological stress sceneries.
Aim 1 will determine if deletion of both ROCK1 and ROCK2 from adult cardiomyocytes limits the progression of heart failure in pathological hypertrophy and myocardial ischemic injury through activating autophagy and facilitating autophagic flux by inhibiting mTOR signaling.
Aim 2 will determine if deletion of both ROCK1 and ROCK2 from adult fibroblasts limits the activation of myofibroblasts and fibrotic response through inhibition of F-actin regulated transcription factor activation including the serum response factor (SRF) and myocardin-related transcription factors (MRTFs); the direct contribution of ROCKs/F-actin/MRTFs/SRF axis in fibroblasts to cardiac fibrosis has never been demonstrated in vivo, and our preliminary results indicate that the inducible approach is required for double ROCK knockout in fibroblasts. The biomedical significance of this work is to provide the cutting-edge concepts for understanding pathophysiological roles of ROCKs in heart failure. The ultimate goal is to develop new therapeutic intervention to ameliorate compromised cardiac function.
Heart failure (HF) is a leading cause of death, but the prevention and treatment remain challenging. Since Rho kinase (ROCK1 and ROCK2) has recently emerged as a potential therapeutic target, the proposed research focus on the pathologic roles of ROCK1 and ROCK2 in HF by deleting both ROCKs in cardiomyocytes and/or fibroblasts. The information obtained from this study can establish the potential therapeutic effects by targeting Rho kinase activity to mitigate heart failure progression.
