Modulation of Adverse Cardiac Remodeling by STARS, a Mediator of MEF2 Signaling and SRF Activity

J Clin Invest. 2007 May;117(5):1324-34. doi: 10.1172/JCI31240. Epub 2007 Apr 5.

Abstract

Cytoskeletal proteins have been implicated in the pathogenesis of cardiomyopathy, but how the cytoskeleton influences the transcriptional alterations associated with adverse cardiac remodeling remains unclear. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein localized to the Z disc that activates serum response factor-dependent (SRF-dependent) transcription by inducing nuclear translocation of the myocardin-related SRF coactivators MRTF-A and -B. We show that STARS expression is upregulated in mouse models of cardiac hypertrophy and in failing human hearts. A conserved region of the STARS promoter containing an essential binding site for myocyte enhancer factor-2 (MEF2), a stress-responsive transcriptional activator, mediates cardiac expression of STARS, which in turn activates SRF target genes. Forced overexpression of STARS in the heart sensitizes the heart to pressure overload and calcineurin signaling, resulting in exaggerated deterioration in cardiac function in response to these hypertrophic stimuli. These findings suggest that STARS modulates the responsiveness of the heart to stress signaling by functioning as a cytoskeletal intermediary between MEF2 and SRF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cardiomegaly / physiopathology
  • Cell Line
  • Cells, Cultured
  • Cytoskeleton / metabolism
  • Cytoskeleton / pathology
  • Female
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins / biosynthesis
  • Microfilament Proteins / genetics
  • Microfilament Proteins / physiology*
  • Middle Aged
  • Mutagenesis, Site-Directed
  • Myogenic Regulatory Factors / metabolism*
  • Rats
  • Serum Response Factor / metabolism*
  • Signal Transduction* / genetics
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Up-Regulation / genetics
  • Ventricular Remodeling* / genetics

Substances

  • ABRA protein, human
  • Abra protein, mouse
  • Microfilament Proteins
  • Myogenic Regulatory Factors
  • Serum Response Factor
  • Transcription Factors