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(Circulation Research. 2005;96:558.)
© 2005 American Heart Association, Inc.

Cellular Biology

Matrix Protein–Specific Regulation of Cx43 Expression in Cardiac Myocytes Subjected to Mechanical Load

Amit J. Shanker, Kiyomi Yamada, Karen G. Green, Kathryn A. Yamada, Jeffrey E. Saffitz

From the Departments of Pathology and Medicine and the Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Mo.

Correspondence to Jeffrey E. Saffitz, MD, PhD, Department of Pathology, Box 8118, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO 63110. E-mail saffitz{at}pathology.wustl.edu

To elucidate mechanisms responsible for mechanotransduction in the heart and define the effects of remodeling of the extracellular matrix, we cultured neonatal rat ventricular myocytes on native type I collagen, fibronectin, or denatured collagen and subjected them to uniaxial, pulsatile stretch. Changes in expression of the cardiac gap junction protein, Cx43, were measured by confocal microscopy and immunoblotting. Cells grown on fibronectin or denatured collagen exhibited significantly greater Cx43 expression than cells grown on native collagen. Stretch induced a 2-fold increase in Cx43 expression in cells grown on native collagen but no increase in cells grown on fibronectin or denatured collagen. Incubation of cells on native collagen with a peptide containing the arginine-glycine-aspartate (RGD) motif upregulated Cx43 expression equivalent to that induced by stretch. Nonselective activation of integrin signaling with MnCl₂ also upregulated Cx43 expression in cells grown on native collagen. This effect was blocked completely by pretreatment with anti-ß₁ integrin antibody but not by anti-ß₃ integrin antibody. Stretch led to a marked increase in ß₁ integrin immunofluorescent signal in cells grown on native collagen but not in cells grown on fibronectin or denatured collagen. Stretch-induced upregulation of Cx43 was also blocked by anti-ß₁ integrin antibody. Thus, matrix protein-myocyte interactions regulate Cx43 expression via ß₁ integrin signaling initiated by mechanical stimulation in cells grown on native type I collagen, or by RGD-integrin signaling independent of mechanical stress in cells grown on fibronectin or denatured collagen. Changes in the composition of the extracellular matrix may affect electrical coupling in cardiac myocytes.

Key Words: cell culture • connexin43 expression • extracellular matrix • mechanical stretch • mechanotransduction

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