Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 39, Pages 14495-14500Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0601911103
Keywords
heart failure; left ventricle assist device; phosphatase and tensin homolog deleted on chromosome ten
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Funding
- NHLBI NIH HHS [P01 HL 42550, P01 HL085098, P01 HL 49953, R01 HL 72897, R01 HL072897-03, P01 HL042550, R01 HL 64356, P01 HL049953, P01 HL085098-01A10002, R01 HL072897] Funding Source: Medline
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Rho-associated coiled-coil protein kinase 1 (ROCK-11) 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-11 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-11 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-11 cleaved fragment. This constitutively active ROCK-11 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-11-null mice (Rock-1(-/-)) showed a marked reduction in myocyte apoptosis associated with pressure overload. These data suggest an obligatory role for ROCK-11 cleavage in promoting apoptotic signals in myocardial hypertrophy and/or failure.
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