Corin Overexpression Improves Cardiac Function, Heart Failure, and Survival in Mice With Dilated Cardiomyopathy

Heart failure, caused by dilated cardiomyopathy and other cardiac disorders such as hypertension, is a major public health problem with high morbidity and mortality. Corin, a cardiac enzyme that cleaves natriuretic peptides, is a promising biomarker of cardiomyopathy and heart failure, but its functional role in these processes is not understood. We evaluated the potential effects of corin in mice with a well-characterized model of dilated cardiomyopathy. Mice with dilated cardiomyopathy developed heart failure, reduced contractile function, cardiac fibrosis, and accelerated mortality in the setting of low corin expression. In wild-type mice, transgenic, cardiac-targeted, overexpression of corin enhanced cyclic guanosine monophosphate and blood pressure responses to pro-atrial natriuretic peptide, but did not affect heart size, contractility, body weights, survival, and blood pressure. In mice with dilated cardiomyopathy, corin overexpression significantly reduced the development of myocardial fibrosis ( P <0.05). Corin overexpression also enhanced heart contractile function (fractional shortening and ejection fraction; P <0.01) and it significantly reduced heart failure as assessed by lung water ( P <0.05) and alveolar congestion ( P <0.001). Consistent with these observations, corin overexpression significantly prolonged life in mice with dilated cardiomyopathy ( P <0.0001). These results provide the first experimental evidence that corin expression plays a role in cardiomyopathy by modulating myocardial fibrosis, cardiac function, heart failure, and survival.