Abstract 12675: Cardiac Specific Overexpression of Dominant-Negative Rho-kinase Suppresses Pressure Overload Induced Right Ventricular Failure in Mice
Background: Although right ventricular (RV) dysfunction is the leading cause of death in patients with pulmonary arterial hypertension (PAH), no direct cure has yet been developed.We and others have previously demonstrated that Rho-kinase is involved in the molecular mechanisms of cardiovascular hypertrophy/fibrosis and inflammatory responses in various cardiovascular diseases, including heart failure. However, it remains to be examined whether cardiac Rho-kinase activity is directly involved in the development of RV failure. In the present study, we thus examined whether cardiac Rho-kinase plays an important role in the pathogenesis of pressure overload-induced RV failure in mice in vivo.
Methods and Results: We newly generated cardiac (α-MHC)-specific overexpression of dominant-negative Rho-kinase (DN-ROCK) mice, in which myocardial Rho-kinase activity is selectively decreased by 30%. In order to create pressure overload-induced RV failure, we performed severe pulmonary artery constriction (PAC) in male DN-ROCK mice and control littermates. At 4 weeks after PAC, we performed hemodynamic and histological examinations. In control littermates with PAC, RV and liver weights were significantly increased and RV failure with RV dilatation and dysfunction was developed. However, the PAC-induced RV dysfunction was significantly ameliorated in DN-ROCK mice. Furthermore, long-term survival (for 4 weeks after PAC) was significantly ameliorated in DN-ROCK mice compared with control littermates (97% vs. 88%, n=68 each, P≤0.05). Histologically, PAC-induced RV hypertrophy and myocardial interstitial fibrosis were significantly suppressed in DN-ROCK mice compared with control littermates. Importantly, PAC significantly up-regulated protein expression of cardiac Rho-kinase and enhanced phosphorylated ERK/GATA-4 activities in cardiomyocytes in control littermates, whereas those changes were significantly inhibited in DN-ROCK mice.
Conclusions: These results indicate that cardiac Rho-kinase activation is substantially involved in the pathogenesis of pressure overload-induced RV failure, suggesting that Rho-kinase could be a novel therapeutic target of the disorder.
- © 2013 by American Heart Association, Inc.