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 β1D-integrin (β1D) is expressed exclusively in cardiac and skeletal muscle, we hypothesized that β1D 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 ) β1D protein expression was upregulated perinatally; 2 ) α1-adrenergic stimulation of cardiac myocytes increased β1D protein levels 350% and altered its cellular distribution; 3 ) adenovirally mediated overexpression of β1D stimulated cellular reorganization, increased cell size by 250%, and induced molecular markers of the hypertrophic response; and 4 ) overexpression of free β1D cytoplasmic domains inhibited α1-adrenergic cellular organization and atrial natriuretic factor (ANF) expression. Additionally, FAK was linked to the hypertrophic response as follows: 1 ) coimmunoprecipitation of β1D and FAK was detected; 2 ) FAK overexpression induced ANF-luciferase; 3 ) rapid and sustained phosphorylation of FAK was induced by α1-adrenergic stimulation; and 4 ) blunting of the α1-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 β1D and FAK are both components of the hypertrophic response pathway of cardiac myocytes.