Circulation Research. 2002;90:458-464
Published online before print January 24, 2002, doi: 10.1161/hh0402.105790
Published online before print January 24, 2002, doi: 10.1161/hh0402.105790
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Cardiac Myocyte-Specific Excision of the ß1 Integrin Gene Results in Myocardial Fibrosis and Cardiac Failure
From the Departments of Physiology (S.-Y.S., A.E.H., C.J.B., M.C.J., M.O., R.S.R.), Medicine (S.-Y.S., A.E.H., C.J.B., M.O., R.S.R.), Pathology (M.C.F.), and Anesthesia (M.J.); Cardiovascular Research and Mouse Physiology Laboratories (S.-Y.S., A.E.H., C.J.B., M.C.J., M.C.F., M.O., R.S.R.); and Department of Molecular and Medical Pharmacology and Crump Institute for Biological Imaging (T.A.L., D.J.S., S.R.C.), University of California-Los Angeles School of Medicine; Department of Medicine (J.C., K.D.B.), University of California-San Diego School of Medicine; and Mayo Clinic Scottsdale (J.C.L.), Scottsdale, Ariz. Present address for S.R.C. is Department of Biomedical Engineering, University of California-Davis.
Correspondence to Dr 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 ross{at}mednet.ucla.edu
Integrins link the extracellular matrix to the cellular cytoskeleton and serve important roles in cell growth, differentiation, migration, and survival. Ablation of ß1 integrin in all murine tissues results in peri-implantation embryonic lethality. To investigate the role of ß1 integrin in the myocardium, we used Cre-LoxP technology to inactivate the ß1 integrin gene exclusively in ventricular cardiac myocytes. Animals with homozygous ventricular myocyte ß1 integrin gene excision were born in appropriate numbers and grew into adulthood. These animals had 18% of control levels of ß1D integrin protein in the heart and displayed myocardial fibrosis. High-fidelity micromanometer-tipped catheterization of the intact 5-week-old ß1 integrin knockout mice showed depressed left ventricular basal and dobutamine-stimulated contractility and relaxation (LV dP/dtmax and LV dP/dtmin) as compared with control groups (n=8 to 10 of each, P<0.01). Hemodynamic loading imposed by 7 days of transverse aortic constriction showed that the ß1 integrin knockout mice were intolerant of this stress as they had 53% survival versus 88% in controls (n=15 each). By 6 months of age, mice with depressed ventricular expression of ß1 integrin developed a dilated cardiomyopathy that was not evident in any control animals and had patchy decrease in glucose metabolism as determined by positron emission tomography. Myocyte membrane integrity as determined via Evan’s blue dye staining was disrupted in the ß1 integrin knockout mice. This model provides strong evidence for the importance of ß1 integrin in cardiac form and function and indicates that integrins can be linked to development of cardiomyopathies.
Key Words: extracellular matrix • homologous recombination • Cre recombinase • heart • positron emission tomography
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