Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis

• DOI: 10.1073/pnas.0601911103
• Publication Date: 2006-09-19T00:57:41Z
• Authors: Jiang Chang; Min Xie; Viraj R. Shah; Michael D. Schneider; Mark L. Entman; Lei Wei; Robert J. Schwartz
• Keywords: Adult; Heart Failure; Male; 0301 basic medicine; Models, Genetic; Caspase 3; Intracellular Signaling Peptides and Proteins; Apoptosis; Middle Aged; Ceramides; 3. Good health; Enzyme Activation; Disease Models, Animal; Mice; 03 medical and health sciences; Caspases; Animals; Humans; Female; Myocytes, Cardiac; Cells, Cultured; Aged; Demography

Rho-associated coiled-coil protein kinase 1 (ROCK-1) is a direct cleavage substrate of activated caspase-3, which is associated with heart failure. In the course of human heart failure, we found marked cleavage of ROCK-1 resulting in a 130-kDa subspecies, which was absent in normal hearts and in an equivalent cohort of patients with left ventricular assist devices. Murine cardiomyocytes treated with doxorubicin led to enhanced ROCK-1 cleavage and apoptosis, all of which was blocked by a caspase-3 inhibitor. In addition, a bitransgenic mouse model of severe cardiomyopathy, which overexpresses Gq protein and hematopoietic progenitor kinase-/germinal center kinase-like kinase, revealed the robust accumulation of the 130-kDa ROCK-1 cleaved fragment. This constitutively active ROCK-1 subspecies, when expressed in cardiomyocytes, led to caspase-3 activation, indicating a positive feed-forward regulatory loop. ROCK-1-dependent caspase-3 activation was coupled with the activation of PTEN and the subsequent inhibition of protein kinase B (Akt) activity, all of which was attenuated by siRNA directed against ROCK-1 expression. Similarly, ROCK-1-null mice (Rock-1−/−) showed a marked reduction in myocyte apoptosis associated with pressure overload. These data suggest an obligatory role for ROCK-1 cleavage in promoting apoptotic signals in myocardial hypertrophy and/or failure.