Corin is down-regulated and exerts cardioprotective action via activating pro-atrial natriuretic peptide pathway in diabetic cardiomyopathy

Abstract

BackgroundDiabetic cardiomyopathy (DCM), a fatal cardiovascular complication of diabetes mellitus, often leads to progressive heart failure, however its pathogenesis remains unclear. Corin, a cardiac serine protease, is responsible for converting pro-atrial natriuretic peptide (pro-ANP) to biologically active atrial natriuretic peptide (ANP). It has been well established that corin deficiency is associated with the progression of hypertension, cardiac hypertrophy and heart failure. However, because the involvement of corin-mediated pro-ANP processing in DCM has not been clarified, this study aims to investigate the role of corin in the pathogenesis of DCM.MethodsDiabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ 65 mg/kg) to Sprague–Dawley rats (180–220 g). DCM was confirmed by monitoring continuously transthoracic echocardiography every 4 weeks and hemodynamic measurements at 20 weeks. Myocardial disorder and fibrosis were detected by HE staining and Masson’s trichrome staining. The mRNA and protein levels of corin and ANP in rat hearts and cardiomyocytes were determined by quantitative real-time PCR, western blotting and immunohistochemical staining, respectively. H9c2 cardiomyoblasts proliferation was detected by MTT colorimetric assay and viable cell counting with trypan blue. The effect of Corin-siRNA H9c2 cardiomyoblasts on EA.hy926 cells migration was measured by the wound healing scratch assay.ResultsThe corin and ANP expression in mRNA and protein levels was decreased in DCM rat hearts. Corin and ANP levels of neonatal rat cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose were significantly lower than that of normal glucose treated. Precisely, corin and ANP levels decreased in DCM rats at 12, 16, 20 and 33 weeks; neonatal cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose at 36, 48 and 60 h demonstrated significant reduction in corin and ANP levels. Corin-siRNA H9c2 cardiomyoblasts showed decreased proliferation. Culture supernatants of Corin-siRNA H9c2 cardiomyoblasts prevented endothelial cell line EA.hy926 migration in the wound healing scratch assay. Furthermore, iso-lectin expression in arteriole and capillary endothelium was down-regulated in DCM rats.ConclusionsOur results indicate that corin plays an important role in cardioprotection by activating pro-atrial natriuretic peptide pathway in DCM. Corin deficiency leads to endothelial dysfunction and vascular remodeling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0298-9) contains supplementary material, which is available to authorized users.

Corin plays a protective role via upregulating MAPK and downregulating eNOS in diabetic nephropathy endothelial dysfunction

“…15,20 Endothelial dysfunction leads to renal structural and functional abnormalities in DN. 11 Consistently, Jian Wang et al demonstrated that a lack of Corin could inhibit vascular endothelial cell viability. Our previous studies on DCM revealed that Corin from cardiomyocytes affects endothelial cells in a similar fashion.…”

“…11 Examinations including 24-h urine excretion and 24-h urinary albumin and creatinine clearance were monitored. The rats were housed at 22 ± 2°C under a 12:12 lightdark (LD) schedule.…”

“…[6][7][8] Among all tissues, Corin expression in the kidney is second only to that of the heart. 11 Other studies also showed reduced Corin expression in diabetic erectile dysfunction and diabetic cardiovascular complications. 9,10 In our previous study, we demonstrated that Corin expression is decreased in rat hearts with diabetic cardiomyopathy (DCM).…”

The Involvement of Corin in the Progression of Diabetic Erectile Dysfunction in a Rat Model by Down-Regulating ANP /NO/cGMP Signal Pathway

“…However, researchers reported that Corin was elevated in heart transplant patients with ischemic cardiomyopathy and LV concentration of Corin was inversely related to left ventricular ejection fraction [Estefanía et al, ]. To this point, we speculate that Corin expression may differ in different diseases [Pang et al, ]. Besides, Corin activity may not increase even with elevated level of Corin expression because another study showed that cardiac Corin expression was upregulated but activity did not increase in late stages of heart failure (HF) patients and the mouse model of HF [Chen et al, ].…”

“…Interestingly, eNOS and cGMP were also downregulated, indicating the potential role of Corin in NO-associated diabetic ED. Cardiac Corin expression was reduced in both mRNA and protein levels in diabetic cardiomyopathy rats and Corin deficiency exhibited cardiac hypertrophy [Chan et al, 2005;Pang et al, 2015]. Atrial Corin mRNA expression was also downregulated in rats with heart failure [Langenickel et al, 2004].…”