Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

Significance Our data suggest opposite roles for ROCK1 and ROCK2 in cardiomyocytes. Additional studies identified downstream targets of ROCK1 and ROCK2 related to calcium handling, mitochondrial function, and oxidative stress. In particular, our findings indicate that cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary pulmonary hypertension (PH) in cROCK1 −/− mice, while their expressions were lower in cROCK2 −/− mice. Finally, screening of the public chemical library in the Drug Discovery Initiative enabled us to identify compounds that reduce the expressions of CyPA and Bsg. Among them, celastrol suppressed the expression of both CyPA and Bsg in heart and lungs, thereby ameliorating both heart failure and postcapillary PH in mice.