Abstract
Humans with dilated cardiomyopathy (DCM) and heart failure (HF) develop low levels of corin, a multi-domain, cardiac-selective serine protease involved in natriuretic peptide cleavage and sodium and water regulation. However, experimental restoration of corin levels markedly attenuates HF progression. To determine whether the beneficial effects of corin in HF require catalytic activity, we engineered cardiac overexpression of an enzymatically inactive corin transgene (corin-Tg(i)). On a wild-type (WT) background, corin-Tg(i) had no evident phenotypic effects. However, in a well-established genetic model of DCM, corin-Tg(i)/DCM mice had increased survival (p < 0.01 to 0.001) vs. littermate corin-WT/DCM controls. Pleural effusion (p < 0.01), lung edema (p < 0.05), systemic extracellular free water (p < 0.01), and heart weight were decreased (p < 0.01) in corin-Tg(i)/DCM vs. corin-WT/DCM mice. Cardiac ejection fraction and fractional shortening improved (p < 0.01), while ventricular dilation decreased (p < 0.0001) in corin-Tg(i)/DCM mice. Plasma atrial natriuretic peptide, cyclic guanosine monophosphate, and neprilysin were significantly decreased. Cardiac phosphorylated glycogen synthase kinase-3β (pSer9-GSK3β) levels were increased in corin(i)-Tg/DCM mice (p < 0.01). In summary, catalytically inactive corin-Tg(i) decreased fluid retention, improved contractile function, decreased HF biomarkers, and diminished cardiac GSK3β activity. Thus, the protective effects of cardiac corin on HF progression and survival in experimental DCM do not require the serine protease activity of the molecule.
Highlights
Heart failure (HF) is a leading cause of morbidity and mortality that affects an estimated 6.2 million US adults, and the prevalence is predicted to increase to more than 8 million by 2030 [1]
Dilated cardiomyopathy (DCM) is characterized by low cardiac output and progressive heart enlargement with reduced ejection fraction, i.e., a decline in systolic function that leads to overt HFrEF characterized by lung and other types of edema, breathlessness, low cardiac output, and death [4,5]
We reported that plasma corin levels are robustly reduced in patients with acute HFrEF leading to impaired pro-atrial natriuretic peptide (pro-ANP) activation, suggesting that reduced corin levels may contribute, in some individuals, to the sodium and water retention associated with HFrEF [11,14,15,19]
Summary
Heart failure (HF) is a leading cause of morbidity and mortality that affects an estimated 6.2 million US adults, and the prevalence is predicted to increase to more than 8 million by 2030 [1]. Dilated cardiomyopathy (DCM) is a major cause of symptomatic HF and is the most common reason for heart transplantation [2–4]. DCM is characterized by low cardiac output and progressive heart enlargement with reduced ejection fraction (rEF), i.e., a decline in systolic function that leads to overt HFrEF characterized by lung and other types of edema (pleural effusion, ascites, pretibial edema, etc.), breathlessness, low cardiac output, and death [4,5]. Patients at risk for DCM have Stage A HF, but usually progress to Stage B, where there is a decline in heart function; both stages are pre-symptomatic, or prior to the development of symptoms. There is a critical need to discover mechanisms that regulate the development and progression of DCM and HF that might lead to new treatment and prevention strategies
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