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

Jiang Chang, Min Xie, Viraj R. Shah, Michael D. Schneider, Mark L. Entman, Lei Wei, Robert J. Schwartz

Research output: Contribution to journalArticle

155 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)14495-14500
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number39
DOIs
StatePublished - Sep 26 2006

Fingerprint

rho-Associated Kinases
Cardiac Myocytes
Caspase 3
Protein Kinases
Apoptosis
Phosphotransferases
Heart Failure
Gq-G11 GTP-Binding Protein alpha Subunits
Proto-Oncogene Proteins c-akt
Heart-Assist Devices
Caspase Inhibitors
Cardiomyopathies
Doxorubicin
Muscle Cells
Hypertrophy
Small Interfering RNA
Pressure

Keywords

  • Heart failure
  • Left ventricle assist device
  • Phosphatase and tensin homolog deleted on chromosome ten

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis. / Chang, Jiang; Xie, Min; Shah, Viraj R.; Schneider, Michael D.; Entman, Mark L.; Wei, Lei; Schwartz, Robert J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 39, 26.09.2006, p. 14495-14500.

Research output: Contribution to journalArticle

Chang, Jiang ; Xie, Min ; Shah, Viraj R. ; Schneider, Michael D. ; Entman, Mark L. ; Wei, Lei ; Schwartz, Robert J. / Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 39. pp. 14495-14500.
@article{a0cb90d2da924fbb9703bdef4d6e5f57,
title = "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.",
keywords = "Heart failure, Left ventricle assist device, Phosphatase and tensin homolog deleted on chromosome ten",
author = "Jiang Chang and Min Xie and Shah, {Viraj R.} and Schneider, {Michael D.} and Entman, {Mark L.} and Lei Wei and Schwartz, {Robert J.}",
year = "2006",
month = "9",
day = "26",
doi = "10.1073/pnas.0601911103",
language = "English",
volume = "103",
pages = "14495--14500",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "39",

}

TY - JOUR

T1 - Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis

AU - Chang, Jiang

AU - Xie, Min

AU - Shah, Viraj R.

AU - Schneider, Michael D.

AU - Entman, Mark L.

AU - Wei, Lei

AU - Schwartz, Robert J.

PY - 2006/9/26

Y1 - 2006/9/26

N2 - 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.

AB - 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.

KW - Heart failure

KW - Left ventricle assist device

KW - Phosphatase and tensin homolog deleted on chromosome ten

UR - http://www.scopus.com/inward/record.url?scp=33749233824&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749233824&partnerID=8YFLogxK

U2 - 10.1073/pnas.0601911103

DO - 10.1073/pnas.0601911103

M3 - Article

VL - 103

SP - 14495

EP - 14500

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 39

ER -