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.
Highlights
Diabetic cardiomyopathy (DCM), a fatal cardiovascular complication of diabetes mellitus, often leads to progressive heart failure, its pathogenesis remains unclear
Our results indicated that corin exerted cardioprotective action via pro-atrial natriuretic peptide (pro-atrial natriuretic peptide (ANP)) activating pathway in DCM, corin deficiency was associated with endothelial dysfunction and vascular remodeling
Corin and ANP protein levels were decreased after neonatal rat cardiomyocytes were treated with high glucose for 36, 48, 60 h (Fig. 4f–h). These results indicated that the levels of corin and ANP in neonatal rat cardiomyocytes were decreased in a timedependent manner by high glucose treatment
Summary
Diabetic cardiomyopathy (DCM), a fatal cardiovascular complication of diabetes mellitus, often leads to progressive heart failure, its pathogenesis remains unclear. It has been well established that corin deficiency is associated with the progression of hypertension, cardiac hypertrophy and heart failure. Diabetes mellitus (DM) is a chronic, complex disease. The prevalence of diabetes mellitus worldwide continues to increase. The total number of people with diabetes mellitus is estimated to rise from 135 million in 1995 to 300 million in 2025 [1]. Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes, and the leading cause of heart failure and death [2]. DCM is characterized by its effects on cardiac structures and function in the absence of hypertension and coronary artery diseases [3]. To date, knowledge in the pathogenesis of DCM is still limited
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