Abstract 15428: Crucial Role of ROCK1 to Maintain Contractile Cardiac Function in Response to Chronic Pressure-Overload in Mice
Background: Rho-kinase plays a crucial role in the development of cardiac hypertrophy and failure. There are 2 isoforms of Rho-kinase, ROCK1 and ROCK2, with different functions in cardiac tissues (e.g. ECs, VSMCs, cardiomyocytes and cardiac fibroblasts). It has been demonstrated that ROCK2 in cardiomyocytes promotes cardiac hypertrophy and fibrosis in response to pressure-overload. However, the specific roles of ROCK1 in cardiomyocytes remain to be elucidated.
Methods and Results: We newly generated cardiac-specific ROCK1-deficient (KO) mice by Cre-loxP system. We performed transverse aortic constriction (TAC) in wild-type (WT) and ROCK1-KO mice and thereafter examined the time-course for 4 weeks. Importantly, the time-course and localization of ROCK1 and ROCK2 expression after TAC were completely different in WT hearts; ROCK2 was up-regulated in the left ventricular (LV) free wall and ROCK1 in the coronary arterial wall and perivascular area at day7. Western blotting of WT hearts also demonstrated significant up-regulation of ROCK2 expression soon after TAC, whereas ROCK1 was gradually increased after 1 week. Echocardiography showed that ROCK1-KO mice was vulnerable to pressure-overload associated with LV dilatation and reduced contractility (n=8 each, all P<0.05). Histological analysis showed that there was no significant difference in fibrosis. As expected, ROCK1 expression in ROCK1-KO mice was decreased compared with WT mice after TAC (n=10 each, P<0.05), whereas no significant difference in ROCK2 or RhoA was noted. Western blot analyses demonstrated that ROCK1-KO hearts showed increased Akt phosphorylation compared with WT hearts (n=10 each, P<0.05). Furthermore, NOX4 expression was significantly up-regulated in ROCK1-KO hearts compared with WT hearts after TAC (n=10 each, P<0.05). Consistently, dihydroethidium staining showed that the extent of oxidative stress was significantly elevated in ROCK1-KO hearts compared with WT hearts (n=3 each). Finally, ROCK1-KO mice, as compared with WT mice, showed improved survival only in the acute phase but not in the chronic phase.
Conclusions: These results indicate that myocardial ROCK1 plays a crucial role to maintain contractile cardiac function in response to pressure-overload.
Author Disclosures: S. Sunamura: None. K. Satoh: None. K. Suzuki: None. S. Kudo: None. S. Ikeda: None. K. Nobuhiro: None. O. Junichi: None. T. Satoh: None. R. Kurosawa: None. M. Nogi: None. K. Numano: None. T. Shimizu: None. H. Shimokawa: Speakers Bureau; Modest; Daiichi-Sankyo, Bayer Yakuhin.
- © 2016 by American Heart Association, Inc.