ß₁ Integrins Participate in the Hypertrophic Response of Rat Ventricular Myocytes

From the Departments of Physiology (R.S.R., C.P., S.-Y. S.), Medicine (R.S.R., C.P., S.-Y. S., J.I.G.), and The Cardiovascular Research Laboratories, UCLA School of Medicine, Los Angeles, Calif; Department of Vascular Biology (C.F., M.H.G.), Scripps Research Institute, La Jolla, Calif; The Molecular Biology Institute and Department of Biology, San Diego State University (C.C.G.), San Diego, Calif; and Mayo Clinic Scottsdale (J.C.L.), Scottsdale, Ariz.

Correspondence to Robert S. Ross, Department of Physiology, University of California–Los Angeles School of Medicine, Center for the Health Sciences, Room 53–231, 10833 Le Conte Ave, Los Angeles, CA 90095-1751. E-mail rross{at}physiology.medsch.ucla.edu

Abstract—Multiple signaling pathways have been implicated in the hypertrophic response of ventricular myocytes, yet the importance of cell-matrix interactions has not been extensively examined. Integrins are cell-surface molecules that link the extracellular matrix to the cellular cytoskeleton. They can function as cell signaling molecules and transducers of mechanical information in noncardiac cells. Given these properties and their abundance in cardiac cells, we evaluated the hypothesis that ß₁ integrin function is involved in the ₁-adrenergic mediated hypertrophic response of neonatal rat ventricular myocytes. The hypertrophic response of this model required interaction with extracellular matrix proteins. Specificity of these results was confirmed by demonstrating that ventricular myocytes plated onto an anti–ß₁ integrin antibody supported the hypertrophic gene response. Adenovirus-mediated overexpression of ß₁ integrin augmented the myocyte hypertrophic response when assessed by protein synthesis and atrial natriuretic factor production, a marker gene of hypertrophic induction. DNA synthesis was not altered by integrin overexpression. Transfection of cultured cardiac myocytes with either the ubiquitously expressed ß_1A integrin or the cardiac/skeletal muscle–specific ß₁ isoform (ß_1D) activated reporter expression from both the atrial natriuretic factor and myosin light chain-2 ventricular promoters, genetic markers of ventricular cell hypertrophy. Finally, suppression of integrin signaling by overexpression of free ß₁ integrin cytoplasmic domains inhibited the adrenergically mediated atrial natriuretic factor response. These findings show that integrin ligation and signaling are involved in the cardiac hypertrophic response pathway.

Key Words: hypertrophy • myocardium • extracellular matrix • integrin • myocyte

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