Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1

Mark A. Sussman, Sara Welch, Angela Walker, Raisa Klevitsky, Timothy E. Hewett, Robert L. Price, Erik Schaefer, Karen Yager

Research output: Contribution to journalArticle

140 Scopus citations

Abstract

The ras family of small GTP-binding proteins exerts powerful effects upon cell structure and function. One member of this family, rac, induces actin cytoskeletal reorganization in nonmuscle cells and hypertrophic changes in cultured cardiomyocytes. To examine the effect of rac1 activation upon cardiac structure and function, transgenic mice were created that express constitutively activated rac1 specifically in the myocardium. Transgenic rac1 protein was expressed at levels comparable to endogenous rac levels, with activation of the rac1 signaling pathway resulting in two distinct cardiomyopathic phenotypes: a lethal dilated phenotype associated with neonatal activation of the transgene and a transient cardiac hypertrophy seen among juvenile mice that resolved with age. Neither phenotype showed myofibril disarray and hypertrophic hearts were hypercontractilein working heart analyses. The rac1 target p21-activated kinase translocated from a cytosolic to a cytoskeletal distribution, suggesting that rac1 activation was inducing focal adhesion reorganization. Corroborating results showed altered localizations of src in dilated cardiomyopathy and paxillin in both cardiomyopathic phenotypes. This study, the first examination of rac1- mediated cardiac effects in vivo, demonstrates that dilation and hypertrophy can share a common molecular origin and presents evidence that both timing and concurrent signaling from multiple pathways can influence cardiac remodeling.

Original languageEnglish (US)
Pages (from-to)875-886
Number of pages12
JournalJournal of Clinical Investigation
Volume105
Issue number7
DOIs
StatePublished - Apr 2000

ASJC Scopus subject areas

  • Medicine(all)

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