Cardiac Myocyte-Specific Excision of the β1 Integrin Gene Results in Myocardial Fibrosis and Cardiac Failure

Abstract

Integrins link the extracellular matrix to the cellular cytoskeleton and serve important roles in cell growth, differentiation, migration, and survival. Ablation of β1 integrin in all murine tissues results in peri-implantation embryonic lethality. To investigate the role of β1 integrin in the myocardium, we used Cre-LoxP technology to inactivate the β1 integrin gene exclusively in ventricular cardiac myocytes. Animals with homozygous ventricular myocyte β1 integrin gene excision were born in appropriate numbers and grew into adulthood. These animals had 18% of control levels of β1D integrin protein in the heart and displayed myocardial fibrosis. High-fidelity micromanometer-tipped catheterization of the intact 5-week-old β1 integrin knockout mice showed depressed left ventricular basal and dobutamine-stimulated contractility and relaxation (LV dP/dt max and LV dP/dt min ) 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 β1 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 β1 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 β1 integrin knockout mice. This model provides strong evidence for the importance of β1 integrin in cardiac form and function and indicates that integrins can be linked to development of cardiomyopathies.