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(Circulation Research. 2008;102:1109.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Combined Deficiency of Dystrophin and β1 Integrin in the Cardiac Myocyte Causes Myocardial Dysfunction, Fibrosis and Calcification

Laila Elsherif^*, Michael S. Huang^*, Shaw-Yung Shai, Yuan Yang, Rita Y. Li, June Chun, Majid A. Mekany, Andrew L. Chu, Stephen J. Kaufman, Robert S. Ross

From the Department of Medicine (L.E., M.S.H., R.Y.L., J.C., M.A.M., A.L.C., R.S.R.), University of California at San Diego School of Medicine, La Jolla; Veterans Administration San Diego Healthcare System (L.E., M.S.H., Y.Y., R.Y.L., J.C., R.S.R.), Calif; Department of Medicine (S.-Y.S.), Tulane University, New Orleans, La; and Department of Cell and Developmental Biology (S.J.K.), University of Illinois, Urbana. Present address for M.S.H.: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles.

Correspondence to Robert S. Ross, Veterans Administration San Diego Healthcare System, 3350 La Jolla Village Dr, Cardiology Section, 111A, San Diego, CA 92161. E-mail rross{at}ucsd.edu

The dystrophin–glycoprotein complex is a large complex of membrane-associated proteins linking the cytoskeleton to the extracellular matrix in muscle. Transmembrane heterodimeric (β) integrins serve also as cellular adhesion molecules and mechanotransducers. In the animal model for Duchenne muscular dystrophy, the mdx mouse, loss of dystrophin causes more severe abnormalities in skeletal than in cardiac muscle. We hypothesized that ablation of cardiac myocyte integrins in the mdx background would lead to a severe cardiomyopathic phenotype. Mdx mice were crossed to ones with cardiac myocyte-specific deletion of β1 integrin (β1KO) to generate β1KOmdx. Unstressed β1KOmdx mice were viable and had normal cardiac function; however, high mortality was seen in peri- and postpartum females by 6 months of age, when severe myocardial necrosis and fibrosis and extensive dystrophic calcification was seen. Decreased ventricular function and blunted adrenergic responsiveness was found in the β1KOmdx mice compared with control (Lox/Lox, no Cre), β1KO, and mdx. Similarly, adult β1KOmdx males were more prone to isoproterenol-induced heart failure and death compared with control groups. Given the extensive calcification, we analyzed transcript levels of genes linked to fibrosis and calcification and found matrix -carboxyglutamic acid protein, decorin, periostin, and the osteoblast transcription factor Runx2/Cbfa1 significantly increased in β1KOmdx cardiac muscle. Our data show that combined deficiency of dystrophin and integrins in murine cardiac myocytes results in more severe cardiomyopathic changes in the stressed myocardium than reduction of either dystrophin or integrins alone and predisposes to myocardial calcification.

Key Words: Integrin • muscular dystrophy • dystrophin • heart failure • calcification