Heart failure remains a leading cause of human morbidity and mortality. Rho kinase (also named ROCK) has recently emerged as a potential therapeutic target for the treatment of cardiac diseases with the overall promising studies showing beneficial effects of ROCK inhibitors in experimental and clinical studies. However, one important question needing to be addressed is whether ROCK truly represents a viable target for the treatment of human disease as currently available ROCK inhibitors have broad specificity. In addition, the two members of the ROCK family, ROCK1 and ROCK2, are inhibited by ROCK inhibitors with equal potency, and little is known about ROCK isoform functions in vivo. We recent discovered that systemic ROCK1 deficiency is protective against cardiac decompensation and the anti-apoptotic effect of ROCK1 deficiency is a critical contributor. In contrast to the beneficial effects of ROCK1 deletion, we observed that cardiac-specific ROCK2 deficiency results in spontaneous cardiac hypertrophy and dysfunction, suggesting a novel role for ROCK2 in cardiac protection. Our in vitro studies using ROCK1 or ROCK2 deficient embryo-derived fibroblasts support a novel mechanistic concept that ROCK1 preferentially mediates stress-induced acto-myosin contraction via the ROCK1/MYPT/MLC pathway leading to increased cell death, while ROCK2 preferentially contributes to actin polymerization via the ROCK2/LIMK/cofilin pathway leading to improved cell survival under stress conditions. The goal of this application is to dissect isoform functions of ROCK in hypertrophic cardiac remodeling and to test a novel central hypothesis that ROCK1 and ROCK2 are functionally different in regulating cardiomyocyte death and cardiac remodeling in response to cardiac stress.
Specific Aim 1 will test the hypothesis that ROCK2 promotes cardiomyocyte survival and cardiac protection. The studies will further characterize the onset and progression of spontaneous cardiac hypertrophy in cardiac-specific ROCK2 knockout mice, and will determine if conditional ROCK2 deletion in cardiomyocytes accelerates heart failure progression.
Specific Aim 2 will determine the ultimate role of ROCK1 in cardiac decompensation. The studies will determine if conditional ROCK1 deletion in cardiomyocytes can limit the progression of heart failure when cardiac hypertrophy or dilated cardiomyopathy has already occurred through chronic pressure overload.
Specific Aim 3 will test the hypothesis that ROCK1 and ROCK2 play opposite roles in mediating stress-induced cardiomyocyte death and characterize the underlying mechanisms. Results of these studies will significantly advance our knowledge in ROCK isoform pathophysiology and inform clinical trials testing ROCK pan- inhibitors, and eventually isoform selective inhibitors, with the ultimate goal of developing therapeutic interventions to prevent cardiomyocyte death and reduce heart failure progression.

Public Health Relevance

Heart failure is a leading cause of human morbidity and mortality. This application will explore how the two members of Rho kinase family, ROCK1 and ROCK2, differently regulate cardiomyocyte death and progression of heart failure. The information gained from this study should help us to better understand the beneficial and side effects of clinically approved Rho kinase inhibitors (which suppress both ROCK1 and ROCK2) with the ultimate goal of developing therapeutic interventions to prevent cardiomyocyte death and reduce heart failure progression.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL107537-02
Application #
8665458
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wang, Lan-Hsiang
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Surma, Michelle; Handy, Caitlin; Chang, Jiang et al. (2014) ROCK1 deficiency enhances protective effects of antioxidants against apoptosis and cell detachment. PLoS One 9:e90758
Lee, Seung-Hwan; Huang, Hu; Choi, Kangduk et al. (2014) ROCK1 isoform-specific deletion reveals a role for diet-induced insulin resistance. Am J Physiol Endocrinol Metab 306:E332-43