Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy

Kenneth E. Richardson, Paul Tannous, Kambeez Berenji, Bridgid Nolan, Kayla J. Bayless, George E. Davis, Beverly A Rothermel, Joseph A Hill

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

There is great interest in deciphering mechanisms of maladaptive remodeling in cardiac hypertrophy in the hope of affording clinical benefit. Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rad and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about the interaction-if any-between these important signaling molecules in hypertrophic heart disease. In this study, we examined the molecular interplay among these molecules, finding that Rho family guanosine triphosphatase signaling occurs either downstream of calcineurin or as a required, parallel pathway. It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition blocks hypertrophy, and we report here that "statin" therapy effectively suppresses small G protein activation and blunts hypertrophic growth in vitro and in vivo. Importantly, despite significant suppression of hypertrophy, clinical and hemodynamic markers remained compensated, suggesting that the hypertrophic growth induced by this pathway is not required to maintain circulatory performance.

Original languageEnglish (US)
Pages (from-to)414-424
Number of pages11
JournalJournal of Investigative Medicine
Volume53
Issue number8
DOIs
Publication statusPublished - Dec 2005

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Keywords

  • Calcineurin
  • Hypertrophy
  • Signal transduction
  • Small G proteins
  • Statins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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