Abstract 533: Crucial Role of Rho-Kinase in Pressure Overload--Induced Right Ventricular Hypertrophy and Dysfunction in Mice: A Possible Novel Therapeutic Target of Right Ventricular Failure

Rationale: Right ventricular (RV) failure is the leading cause of death in various cardiopulmonary diseases, including pulmonary hypertension. It is generally considered that the RV is vulnerable to pressure-overload as compared with the left ventricle (LV). However, as compared with LV failure, the molecular mechanisms of RV failure are poorly understood. Objective: We aimed to identify molecular therapeutic targets for RV failure in a mouse model of pressure-overload. Methods and Results: To induce pressure-overload to respective ventricles, we performed pulmonary artery constriction (PAC) or transverse aortic constriction (TAC) in mice. We first performed microarray analysis and found that the molecules related to RhoA/Rho-kinase and integrin pathways were significantly up-regulated in the RV with PAC compared with the LV with TAC. Then, we examined the responses of both ventricles to chronic pressure-overload in vivo. We demonstrated that compared with TAC, PAC caused greater extents of mortality, Rho-kinase expression (especially ROCK2 isoform) and oxidative stress in pressure-overloaded RV, reflecting the weakness of the RV in response to pressure-overload. Additionally, mechanical stretch of RV cardiomyocytes from rats immediately up-regulated ROCK2 expression (not ROCK1), suggesting the specific importance of ROCK2 in stretch-induced responses of RV tissues. Furthermore, mice with myocardial-specific overexpression of dominant-negative Rho-kinase (DN-RhoK) showed resistance to pressure-overload-induced hypertrophy and dysfunction associated with reduced oxidative stress. Finally, DN-RhoK mice showed a significantly improved long-term survival in both PAC and TAC as compared with littermate controls. Conclusions: These results indicate that the Rho-kinase pathway plays a crucial role in RV hypertrophy and dysfunction, suggesting that the pathway is a novel therapeutic target of RV failure in humans.