Abstract 1221: Targeted Deletion of ROCK2 in Cardiomyocytes Prevents Angiotensin II-Induced Cardiac Hypertrophy
Background - Previous studies have shown that Rho kinase (ROCK) inhibitors prevent the development of cardiac hypertrophy. Because ROCK inhibitors inhibit both ROCK isoforms, ROCK1 and ROCK2, the isoform-specific role of ROCK cannot be elucidated from these studies. Hence, a genetic approach with targeted deletion of ROCK in cardiomyocytes provides the best opportunity towards understanding the role of ROCK isoforms in the development of cardiac hypertrophy. Previous studies showed that ROCK1 KO mice develop cardiac hypertrophy to angiotensin II infusion similar to WT mice, but do not develop cardiac fibrosis. However, the role of ROCK2 in the development of cardiac hypertrophy remains to be determined.
Methods and Results - Mice deficient in cardiomyocyte-specific ROCK2 (c-ROCK2−/−) were generated by crossing mice with loxP-flanked ROCK2 allele with transgenic mice expressing a Cre protein under the control of the cardiomyocyte-specific alpha-myosin heavy chain promoter. The ROCK2 expression levels in the c-ROCK2−/− mice heart was decreased to less than 30% compared with wild-type mice (ROCK2+/+ mice) in the whole heart. Heart rate, blood pressures and cardiac systolic function were normal in c-ROCK2−/− mice. Ang II (400ng/kg/min) or vehicle was subcutaneously infused into c-ROCK2−/− and ROCK2+/+ male mice (each group; n=10) for 28 days. Ang II-induced cardiac hypertrophy assessed by an increase in heart weight, left ventricular mass, myocyte cross-sectional area and cardiac hypertrophy-related genes expressions were attenuated in c-ROCK2−/− mice compared with ROCK2+/+ mice. The basal activity of extracellular signal-regulated kinase (ERK) were similar in hearts between two groups but the activation of ERK was attenuated and the activity was downregulated earlier in c-ROCK2−/− than in ROCK2+/+ mice. The activity of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK) and Akt activity were similar between two groups.
Conclusions - These results indicate that ROCK2 is necessary for Ang II-induced cardiac hypertrophy. The mechanism, in part, involves the activation of ERK by ROCK2. Thus, selective ROCK2 inhibitors may be beneficial for preventing cardiac hypertrophy.