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(Circulation Research. 2006;99:636.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Myocyte-Restricted Focal Adhesion Kinase Deletion Attenuates Pressure Overload–Induced Hypertrophy

Laura A. DiMichele, Jason T. Doherty, Mauricio Rojas, Hilary E. Beggs, Louis F. Reichardt, Christopher P. Mack, Joan M. Taylor

From the Departments of Pathology and Laboratory Medicine (L.A.D., J.T.D., C.P.M., J.M.T.) and Medicine (M.R.) and the Carolina Cardiovascular Biology Center (M.R., C.P.M., J.M.T.), University of North Carolina, Chapel Hill; and Howard Hughes Medical Institute and Departments of Ophthalmology (H.E.B.) and Physiology (H.E.B., L.F.R.), University of California, San Francisco.

Correspondence to Joan M. Taylor, Department of Pathology and Laboratory Medicine, 501 Brinkhous-Bullitt Bldg, CB 7525, University of North Carolina, Chapel Hill, NC 27599. E-mail jmt3x{at}med.unc.edu

Focal adhesion kinase (FAK) is a ubiquitously expressed cytoplasmic tyrosine kinase strongly activated by integrins and neurohumoral factors. Previous studies have shown that cardiac FAK activity is enhanced by hypertrophic stimuli before the onset of overt hypertrophy. Herein, we report that conditional deletion of FAK from the myocardium of adult mice did not affect basal cardiac performance, myocyte viability, or myofibrillar architecture. However, deletion of FAK abolished the increase in left ventricular posterior wall thickness, myocyte cross-sectional area, and hypertrophy-associated atrial natriuretic factor induction following pressure overload. Myocyte-restricted deletion of FAK attenuated the initial wave of extracellular signal-regulated kinase activation and cFos expression induced by adrenergic agonists and biomechanical stress. In addition, we found that persistent challenge of mice with myocyte-restricted FAK inactivation leads to enhanced cardiac fibrosis and cardiac dysfunction in comparison to challenged genetic controls. These studies show that loss of FAK impairs normal compensatory hypertrophic remodeling without a concomitant increase in apoptosis in response to cardiac pressure overload and highlight the possibility that FAK activation may be a common requirement for the initiation of this compensatory response.

Key Words: FAK • integrins • heart • hypertrophy • heart failure • signaling

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