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

Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14495-500. doi: 10.1073/pnas.0601911103. Epub 2006 Sep 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Models, Genetic
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / drug effects
  • PTEN Phosphohydrolase / metabolism
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Systole / physiology
  • rho-Associated Kinases

Substances

  • 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