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

Abstract

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.

• Authors: Jiang Chang, Min Xie, Viraj R Shah, Michael D Schneider, Mark L Entman, Lei Wei, Robert J Schwartz
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 39 Pg. 14495-500 (Sep 26 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16983089 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ceramides
• Intracellular Signaling Peptides and Proteins
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• rho-Associated Kinases
• PTEN Phosphohydrolase
• PTEN protein, human
• CASP3 protein, human
• Casp3 protein, mouse
• Casp3 protein, rat
• Caspase 3
• Caspases

Topics

• Adult
• Aged
• Animals
• Apoptosis (drug effects)
• Caspase 3
• Caspases (metabolism)
• Cells, Cultured
• Ceramides (pharmacology)
• Demography
• Disease Models, Animal
• Enzyme Activation
• Female
• Heart Failure (enzymology)
• Humans
• Intracellular Signaling Peptides and Proteins (chemistry, deficiency, metabolism)
• Male
• Mice
• Middle Aged
• Models, Genetic
• Myocytes, Cardiac (cytology, drug effects)
• PTEN Phosphohydrolase (metabolism)
• Protein Serine-Threonine Kinases (chemistry, deficiency, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Systole (physiology)
• rho-Associated Kinases