title: Corin is down-regulated and exerts cardioprotective action via activating pro-atrial natriuretic peptide pathway in diabetic cardiomyopathy.
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.
authors.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.
authors.forename: Aiming
authors.initials: A
authors.lastname: Pang
authors.affiliation: School of Medical Laboratory, Tianjin Medical University, No. 1 Guangdong Road, Hexi District, Tianjin, 300203, China. huyahui1990@163.com.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Medical Laboratory, Tianjin Medical University, No. 1 Guangdong Road, Hexi District, Tianjin, 300203, China. pfzhoucn@163.com.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Zhou
authors.affiliation: School of Medical Laboratory, Tianjin Medical University, No. 1 Guangdong Road, Hexi District, Tianjin, 300203, China. SZWLGFZAYS@163.com.
authors.forename: Guangfeng
authors.initials: G
authors.lastname: Long
authors.affiliation: School of Medical Laboratory, Tianjin Medical University, No. 1 Guangdong Road, Hexi District, Tianjin, 300203, China. tianxin73@live.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: School of Medical Laboratory, Tianjin Medical University, No. 1 Guangdong Road, Hexi District, Tianjin, 300203, China. menli1977@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Men
authors.affiliation: School of Medical Laboratory, Tianjin Medical University, No. 1 Guangdong Road, Hexi District, Tianjin, 300203, China. shenyanna@sina.com.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Shen
authors.affiliation: School of Medical Laboratory, Tianjin Medical University, No. 1 Guangdong Road, Hexi District, Tianjin, 300203, China. yundeliu@126.com.
authors.forename: Yunde
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Medical Laboratory, Tianjin Medical University, No. 1 Guangdong Road, Hexi District, Tianjin, 300203, China. yujiecui@hotmail.com.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Cui
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D007150:Immunohistochemistry; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing
chemical_list: D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D012697:Serine Endopeptidases; C492879:corin protein, rat