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

Pang A, Hu Y, Zhou P, Long G, Tian X, Men L, Shen Y, Liu Y, Cui Y - Cardiovasc Diabetol (2015)

Bottom Line: The effect of Corin-siRNA H9c2 cardiomyoblasts on EA.hy926 cells migration was measured by the wound healing scratch assay.The corin and ANP expression in mRNA and protein levels was decreased in DCM rat hearts.Corin-siRNA H9c2 cardiomyoblasts showed decreased proliferation.

View Article: PubMed Central - PubMed

Affiliation: Hematopoietic Stem Cell Transplantation Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, 300020, China. aimingpangdoc@live.cn.

ABSTRACT

Background: Diabetic 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.

Methods: Diabetes 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.

Results: The 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.

Conclusions: Our 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.

No MeSH data available.


Related in: MedlinePlus

Transmission electron microscopy of Ctrl and DCM rat hearts. Bar 400 nm (i, ii), bar 325 nm (ii, iv). i, iii The ultrastructure of cardiomyocyte in Ctrl rats showed typical symmetric myofibrils, clear outline of mitochondria, integrated mitochondrial membrane and well-organized cristae. ii, iv The ultrastructure of cardiomyocyte in DCM rats showed severe mitochondria damage, disordered myofibrils arrangement
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Fig2: Transmission electron microscopy of Ctrl and DCM rat hearts. Bar 400 nm (i, ii), bar 325 nm (ii, iv). i, iii The ultrastructure of cardiomyocyte in Ctrl rats showed typical symmetric myofibrils, clear outline of mitochondria, integrated mitochondrial membrane and well-organized cristae. ii, iv The ultrastructure of cardiomyocyte in DCM rats showed severe mitochondria damage, disordered myofibrils arrangement

Mentions: DCM rats presented higher blood glucose (22.4–33.3 mmol/L), while that of control group was maintained at normal level (Fig. 1a). Body weights were decreased in DCM rats compared with those in the control group at the same point in time (Fig. 1b). The urine glucose test of DCM rats was consistently positive (Data were not shown). At the same time, haematoxylin eosin staining showed cardiomyocyte hypertrophy and masson’s trichrome staining displayed interstitial and perivascular fibrosis in DCM rats (Fig. 1c–e). Heart weight to body weight ratio was significantly increased in DCM rats in comparison to that in the control group (Fig. 1f). The changes of cardiac structure and cardiac dysfunction were assessed by echocardiography (Fig. 1g–m) and hemodynamic measurements (Fig. 1n–p) in two groups. DCM rats showed impairment of cardiomyocyte including severe mitochondria damage, disordered myofibrils arrangement (Fig. 2) and excess glycogen deposition (Additional file 1: Figure S1) by transmission electron microscopy.Fig. 1


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

Pang A, Hu Y, Zhou P, Long G, Tian X, Men L, Shen Y, Liu Y, Cui Y - Cardiovasc Diabetol (2015)

Transmission electron microscopy of Ctrl and DCM rat hearts. Bar 400 nm (i, ii), bar 325 nm (ii, iv). i, iii The ultrastructure of cardiomyocyte in Ctrl rats showed typical symmetric myofibrils, clear outline of mitochondria, integrated mitochondrial membrane and well-organized cristae. ii, iv The ultrastructure of cardiomyocyte in DCM rats showed severe mitochondria damage, disordered myofibrils arrangement
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4597453&req=5

Fig2: Transmission electron microscopy of Ctrl and DCM rat hearts. Bar 400 nm (i, ii), bar 325 nm (ii, iv). i, iii The ultrastructure of cardiomyocyte in Ctrl rats showed typical symmetric myofibrils, clear outline of mitochondria, integrated mitochondrial membrane and well-organized cristae. ii, iv The ultrastructure of cardiomyocyte in DCM rats showed severe mitochondria damage, disordered myofibrils arrangement
Mentions: DCM rats presented higher blood glucose (22.4–33.3 mmol/L), while that of control group was maintained at normal level (Fig. 1a). Body weights were decreased in DCM rats compared with those in the control group at the same point in time (Fig. 1b). The urine glucose test of DCM rats was consistently positive (Data were not shown). At the same time, haematoxylin eosin staining showed cardiomyocyte hypertrophy and masson’s trichrome staining displayed interstitial and perivascular fibrosis in DCM rats (Fig. 1c–e). Heart weight to body weight ratio was significantly increased in DCM rats in comparison to that in the control group (Fig. 1f). The changes of cardiac structure and cardiac dysfunction were assessed by echocardiography (Fig. 1g–m) and hemodynamic measurements (Fig. 1n–p) in two groups. DCM rats showed impairment of cardiomyocyte including severe mitochondria damage, disordered myofibrils arrangement (Fig. 2) and excess glycogen deposition (Additional file 1: Figure S1) by transmission electron microscopy.Fig. 1

Bottom Line: The effect of Corin-siRNA H9c2 cardiomyoblasts on EA.hy926 cells migration was measured by the wound healing scratch assay.The corin and ANP expression in mRNA and protein levels was decreased in DCM rat hearts.Corin-siRNA H9c2 cardiomyoblasts showed decreased proliferation.

View Article: PubMed Central - PubMed

Affiliation: Hematopoietic Stem Cell Transplantation Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, 300020, China. aimingpangdoc@live.cn.

ABSTRACT

Background: Diabetic 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.

Methods: Diabetes 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.

Results: The 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.

Conclusions: Our 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.

No MeSH data available.


Related in: MedlinePlus