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

Abstract

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, over-expression 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 over-expression 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 over-expression 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.

Heart Failure

“…It is entirely possible that some of the improvements in cardiac contractility and reduced fibrosis seen in the DCM, corin-Tg mice are secondary to enhanced BNP processing. The hallmark finding of the study by Gladysheva et al 11 is the demonstration that increasing corin expression (and presumably activity) is sufficient to ameliorate the heart failure phenotype in this model of heart failure. It further suggests that corin deficiency state dictates phenotype more so than the heart failure-inducing mutation.…”

“…There was associated increased pro-ANP processing, with reduction in blood pressure and increased cGMP production, although BNP kinetics were not evaluated in detail. 11 Thus it remains unclear what proportion of the observed beneficial effect of corin is secondary to its ANP versus BNP-activating effects. It is entirely possible that some of the improvements in cardiac contractility and reduced fibrosis seen in the DCM, corin-Tg mice are secondary to enhanced BNP processing.…”

“…In view of these findings 11 and the intriguing possibility that corin deficiency may be implicated in other disturbances of vascular constrictor tone such as preeclampsia, 12 modulation of corin expression and activity becomes an attractive therapeutic target.…”

Polyserase-1/TMPRSS9 induces pro-tumor effects in pancreatic cancer cells by activation of pro-uPA

“…Thus, enteropeptidase is produced by the duodenum and its function is essential to digest food efficiently (4). Corin contributes to blood pressure control through activation of atrial natriuretic peptide (5). Matriptase-2 participates in iron homeostasis (6), and hepsin is implicated in the process of hearing (7).…”

Corin as novel biomarker for myocardial infarction

“…The data shown by Zhou et al, however, might reflect the widely accepted long-term deleterious effect of corin deficiency on the cardiovascular system (11). For instance, low corin expression was related with myocardial fibrosis and contractile dysfunction in a murine model of dilated cardiomyopathy (12). Contrary, overexpression of corin could improve cardiac morphology and function.…”