Striated muscle-specific β1D-integrin and FAK are involved in cardiac myocyte hypertrophic response pathway

Alterations in the extracellular matrix occur during the cardiac hypertrophic process. Because integrins mediate cell-matrix adhesion and beta (1D)-integrin (beta 1D) is expressed exclusively in cardiac and skeletal muscle, we hypothesized that beta 1D and focal adhesion kinase (FAK), a proximal integrin-signaling molecule, are involved in cardiac growth. With the use of cultured ventricular myocytes and myocardial tissue, we found the following: 1) beta 1D protein expression was upregulated perinatally; 2) alpha (1)-adrenergic stimulation of cardiac myocytes increased beta 1D protein levels 350% and altered its cellular distribution; 3) adenovirally mediated overexpression of beta 1D stimulated cellular reorganization, increased cell size by 250%, and induced molecular markers of the hypertrophic response; and 4) overexpression of free beta 1D cytoplasmic domains inhibited alpha (1)-adrenergic cellular organization and atrial natriuretic factor (ANF) expression. Additionally, FAK was linked to the hypertrophic response as follows: 1) coimmunoprecipitation of beta 1D and FAK was detected; 2) FAK overexpression induced ANF-luciferase; 3) rapid and sustained phosphorylation of FAK was induced by alpha (1)-adrenergic stimulation; and 4) blunting of the alpha (1)-adrenergically modulated hypertrophic response was caused by FAK mutants, which alter Grb2 or Src binding, as well as by FAK-related nonkinase, a dominant interfering FAK mutant. We conclude that beta 1D and FAK are both components of the hypertrophic response pathway of cardiac myocytes.