Rad GTPase deficiency leads to cardiac hypertrophy

Lin Chang, Jifeng Zhang, Yu Hua Tseng, Chang Qing Xie, Jacob Ilany, Jens C. Brüning, Zhongcui Sun, Xiaojun Zhu, Taixing Cui, Keith A. Youker, Qinglin Yang, Sharlene M. Day, C. Ronald Kahn, Y. Eugene Chen

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

BACKGROUND - Rad (Ras associated with diabetes) GTPase is the prototypic member of a subfamily of Ras-related small G proteins. The aim of the present study was to define whether Rad plays an important role in mediating cardiac hypertrophy. METHODS AND RESULTS - We document for the first time that levels of Rad mRNA and protein were decreased significantly in human failing hearts (n=10) compared with normal hearts (n=3; P<0.01). Similarly, Rad expression was decreased significantly in cardiac hypertrophy induced by pressure overload and in cultured cardiomyocytes with hypertrophy induced by 10 μmol/L phenylephrine. Gain and loss of Rad function in cardiomyocytes significantly inhibited and increased phenylephrine-induced hypertrophy, respectively. In addition, activation of calcium-calmodulin-dependent kinase II (CaMKII), a strong inducer of cardiac hypertrophy, was significantly inhibited by Rad overexpression. Conversely, downregulation of CaMKIIδ by RNA interference technology attenuated the phenylephrine-induced hypertrophic response in cardiomyocytes in which Rad was also knocked down. To further elucidate the potential role of Rad in vivo, we generated Rad-deficient mice and demonstrated that they were more susceptible to cardiac hypertrophy associated with increased CaMKII phosphorylation than wild-type littermate controls. CONCLUSIONS - The present data document for the first time that Rad is a novel mediator that inhibits cardiac hypertrophy through the CaMKII pathway. The present study will have significant implications for understanding the mechanisms of cardiac hypertrophy and setting the basis for the development of new strategies for treatment of cardiac hypertrophy.

Original languageEnglish (US)
Pages (from-to)2976-2983
Number of pages8
JournalCirculation
Volume116
Issue number25
DOIs
StatePublished - Dec 2007

Keywords

  • Cardiomyopathy
  • Genes
  • Heart diseases
  • Hypertrophy
  • Natriuretic peptides

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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