title: Oxidative stress contributes to the impaired sonic hedgehog pathway in type 1 diabetic mice with myocardial infarction.
abstract: Our previous study demonstrated that an impaired sonic hedgehog (Shh) pathway contributed to cardiac dysfunction in type 1 diabetic mice with myocardial infarction (MI). The present study aimed to test the hypothesis that oxidative stress may contribute to the impaired Shh pathway and cardiac dysfunction in type 1 diabetic mice with MI. Streptozotocin-induced type 1 diabetic mice (C57/Bl6, male) and rat neonatal cardiomyocytes were used in the present study. Mice were randomly assigned to undergo ligation of the coronary artery or pseudosurgery. A potent antioxidant Tempol was administeredin vivoandin vitro. Cardiac function was assessed by echocardiography, capillary density by immunohistochemisty, percentage of myocardial infarct using Massons trichrome staining, reactive oxygen species detection using dihydroethidium dye or 2,7-dichlorofluorescein diacetate probe and protein expression levels of the Shh pathway by western blot analysis. The antioxidant Tempol was shown to significantly increase myocardial protein expression levels of Shh and patched-1 (Ptc1) at 7-18 weeks and improved cardiac function at 18 weeks in type 1 diabetic mice, as compared with mice receiving no drug treatment. Furthermore, myocardial protein expression levels of Shh and Ptc1 were significantly upregulated on day 7 after MI, and capillary density was enhanced. In addition, the percentage area of myocardial infarct was reduced, and the cardiac dysfunction and survival rate were improved on day 21 in diabetic mice treated with Tempol.In vitro, treatment of rat neonatal cardiomyocytes with a mixture of xanthine oxidase and xanthine decreased protein expression levels of Shh and Ptc1 in a concentration-dependent manner, and Tempol attenuated this effect. These results indicate that oxidative stress may contribute to an impaired Shh pathway in type 1 diabetic mice, leading to diminished myocardial healing and cardiac dysfunction. Antioxidative strategies aimed at restoring the endogenous Shh pathway may offer a useful means for improving diabetic cardiac function.
authors.affiliation: Department of Pharmacology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China ; Guangzhou Institute of Cardiovascular Disease, Guangzhou Key Laboratory of Cardiovascular Disease, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
authors.forename: Y A
authors.initials: YA
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
authors.forename: Xiao-Ya
authors.initials: XY
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
authors.forename: Li-Shan
authors.initials: LS
authors.lastname: He
authors.affiliation: Guangzhou Research Institute of Snake Venom, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Guangzhou Research Institute of Snake Venom, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: He
authors.affiliation: Department of Pharmacology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.
authors.forename: Gui-Ping
authors.initials: GP
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China ; Guangzhou Institute of Cardiovascular Disease, Guangzhou Key Laboratory of Cardiovascular Disease, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Luo
keywords: diabetes; myocardial infarction; oxidative stress; sonic hedgehog pathway