Endogenous Endothelin-1 Is Required for Cardiomyocyte Survival In Vivo

Background— Endothelin-1 (ET-1) has potent vasoconstrictor and hypertrophic actions. Pharmacological antagonists of endothelin receptors attenuate cardiac hypertrophy, have been approved for treatment of pulmonary hypertension, and are under investigation for treatment of heart failure. To investigate the role of ET-1 in the heart, we created mice with cardiomyocyte deletion of ET-1. Methods and Results— Mice with cardiomyocyte-specific deletion of ET-1 are phenotypically normal when young. Remarkably, as the mice age or when young animals are subjected to aortic banding, they develop an unexpected phenotype of progressive systolic dysfunction and cardiac dilation. Echocardiography, necropsy, histology, and molecular phenotype confirm a dilated cardiomyopathy. Terminal deoxynucleotidyl transferase–mediated dUTP nick-end-labeling analysis reveals greater abundance of apoptotic nuclei in the ET-1–deficient hearts. Transcriptional and Western analyses suggest enhanced tumor necrosis factor (TNF)–mediated apo...