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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, 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.

SUBMITTER: Gladysheva IP

PROVIDER: S-EPMC3728819 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Corin overexpression improves cardiac function, heart failure, and survival in mice with dilated cardiomyopathy.

Gladysheva Inna P IP Wang Dong D McNamee Rachel A RA Houng Aiilyan K AK Mohamad Almois A AA Fan T Michael TM Reed Guy L GL

Hypertension (Dallas, Tex. : 1979) 20121210 2

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 develop ...[more]

PMID: 23232642

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Project description:BackgroundBiased agonism of the angiotensin II receptor is known to promote cardiac contractility. Our laboratory indicated that these effects may be attributable to changes at the level of the myofilaments. However, these signaling mechanisms remain unknown. Because a common finding in dilated cardiomyopathy is a reduction in the myofilament-Ca2+ response, we hypothesized that β-arrestin signaling would increase myofilament-Ca2+ responsiveness in a model of familial dilated cardiomyopathy and improve cardiac function and morphology.MethodsWe treated a dilated cardiomyopathy-linked mouse model expressing a mutant tropomyosin (Tm-E54K) for 3 months with either TRV120067, a β-arrestin 2-biased ligand of the angiotensin II receptor, or losartan, an angiotensin II receptor blocker. At the end of the treatment protocol, we assessed cardiac function using echocardiography, the myofilament-Ca2+ response of detergent-extracted fiber bundles, and used proteomic approaches to understand changes in posttranslational modifications of proteins that may explain functional changes. We also assessed signaling pathways altered in vivo and by using isolated myocytes.ResultsTRV120067- treated Tm-E54K mice showed improved cardiac structure and function, whereas losartan-treated mice had no improvement. Myofilaments of TRV120067-treated Tm-E54K mice had significantly improved myofilament-Ca2+ responsiveness, which was depressed in untreated Tm-E54K mice. We attributed these changes to increased MLC2v and MYPT1/2 phosphorylation seen only in TRV120067-treated mice. We found that the functional changes were attributable to an activation of ERK1/2-RSK3 signaling, mediated through β-arrestin, which may have a novel role in increasing MLC2v phosphorylation through a previously unrecognized interaction of β-arrestin localized to the sarcomere.ConclusionsLong-term β-arrestin 2-biased agonism of the angiotensin II receptor may be a viable approach to the treatment of dilated cardiomyopathy by not only preventing maladaptive signaling, but also improving cardiac function by altering the myofilament-Ca2+ response via β-arrestin signaling pathways.

Dataset Information

Corin overexpression improves cardiac function, heart failure, and survival in mice with dilated cardiomyopathy.

Publications

Corin overexpression improves cardiac function, heart failure, and survival in mice with dilated cardiomyopathy.

Similar Datasets

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