ROCK1 plays an essential role in the transition from cardiac hypertrophy to failure in mice

Jianjian Shi, Yi Wei Zhang, Yu Yang, Lumin Zhang, Lei Wei

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Pathological cardiac hypertrophy caused by diverse etiologies eventually leads to cardiac dilation and functional decompensation. We have recently reported that genetic deletion of Rho-associated coiled-coil containing protein kinase 1 (ROCK1) inhibited several pathological events including cardiomyocyte apoptosis in compensated hypertrophic hearts. The present study investigated whether ROCK1 deficiency can prevent the transition from hypertrophy to heart failure. Transgenic mice with cardiac-restricted overexpression of Gαq develop compensated cardiac hypertrophy at young ages, but progress into lethal cardiomyopathy accompanied by increased apoptosis after pregnancy or at old ages. The studies were first carried out using age- and pregnancy-matched wild-type, Gαq, ROCK1-/-, and Gαq/ROCK1-/- mice. The potent beneficial effect of ROCK1 deletion is demonstrated by abolishment of peripartum mortality, and significant attenuation of left ventricular (LV) dilation, wall thinning, and contractile dysfunction in the peripartum Gαq transgenic mice. Increase in cardiomyocyte apoptosis was suppressed by ROCK1 deletion, associated with increased extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) activation and inhibition of mitochondrial translocation of Bax. In addition, ROCK1 deficiency also improved survival, inhibited cardiomyocyte apoptosis, and preserved LV dimension and function in old Gαq mice at 12months. Furthermore, transgenic overexpression of ROCK1 increased cardiomyocyte apoptosis and accelerated hypertrophic decompensation in Gαq hearts in the absence of pregnancy stress. The present study provides for the first time in vivo evidence for the long-term beneficial effects of ROCK1 deficiency in hypertrophic decompensation and suggests that ROCK1 may be an attractive therapeutic target to limit heart failure progression.

Original languageEnglish (US)
Pages (from-to)819-828
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume49
Issue number5
DOIs
StatePublished - Nov 1 2010

Keywords

  • Apoptosis
  • Bax
  • ERK/MAPK
  • Gαq
  • Heart failure
  • Rho kinase
  • ROCK1

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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