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Different Roles of Myocardial ROCK1 and ROCK2 in Response to Chronic Pressure-Overload in Mice

      Background: Rho-kinase plays a crucial role in the development of cardiac hypertrophy and failure. However, possible different roles of Rho-kinase isoforms, ROCK1 and ROCK2, remain to be elucidated. Methods and Results: We performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient (ROCK1-/-) mice, cardiac-specific ROCK2-deficient (ROCK2-/-) mice, and their littermate controls, and thereafter examined the time-course for 4 weeks. Echocardiography revealed that ROCK1-/- mice were vulnerable to pressure-overload associated with LV dilatation and reduced contractility. In contrast, ROCK2-/- mice showed less LV hypertrophy and preserved LV diastolic function compared with controls after TAC. Histological analysis showed that pressure overload-induced cardiac hypertrophy and fibrosis were enhanced in ROCK1-/- mice compared with controls, whereas cardiac hypertrophy was attenuated in ROCK2-/- mice after TAC. Consistently, ROCK1-/- mice showed poor exercise tolerance, whereas ROCK2-/- mice showed better exercise tolerance compared with controls after TAC. Mechanistic analyses demonstrated that myocardial expressions of ROCK2 and oxidative stress (e.g. NOX2, NOX4, cyclophilin A, basigin) were up-regulated in heart homogenates from ROCK1-/- mice compared with controls after TAC. Furthermore, ROCK1 knockdown by siRNA induced gene expressions of NOX2, NOX4 and p47phox in neonatal rat cardiomyocytes in vitro. Conclusions: These results demonstrate different roles of myocardial ROCK1 and ROCK2 in response to chronic pressure-overload in mice.
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