Circulation: Cardiovascular Genetics HCG Superoxide Dismutase 1 in vivo Ameliorates Maternal Diabetes-Induced Apoptosis and Heart Defects through Restoration of Impaired Wnt Signaling SOD1 blocks diabetes-induced heart defects CIRCCVG/2015/001138-T CIRCCVG/2015/001138-T 10.1161/CIRCGENETICS.115.001138 8 10/20/15 5 Sine Kristina 617-542-5100 617-542-6539 MacRae, Calum Harvard Medical School Dr. Peixin Yang pyang@fpi.umaryland.edu Dr. University of Maryland School of Medicine BRB11-039, 655 West Baltimore Street Baltimore Maryland 21201 UNITED STATES 4107068402 407065474 198410 Fang Wang University of Maryland Baltimore fangwangbox@yahoo.com 268820 Steven A Fisher University of Maryland School of Medicine sfisher1@medicine.umaryland.edu 35108 Jianxiang Zhong University of Maryland Baltimore jzhong@fpi.umaryland.edu 272008 Yanqing Wu University of Maryland Baltimore 805218503@qq.com 268821 Peixin Yang University of Maryland School of Medicine pyang@fpi.umaryland.edu 198410 02/19/2014 02/19/2014 07/10/2015 07/21/2015 08/19/2015 10/20/2015 Original Article maternal diabetes oxidative stress Wnt signaling <P><B><I>Background</I></B>—Oxidative stress is manifested in embryos exposed to maternal diabetes, yet specific mechanisms for diabetes-induced heart defects are not defined. Gene deletion of intermediates of Wingless-related integration (Wnt) signaling causes heart defects similar to those observed in embryos from diabetic pregnancies. We tested the hypothesis that diabetes-induced oxidative stress impairs Wnt signaling thereby causing heart defects, and that these defects can be rescued by transgenic overexpression of the reactive oxygen species scavenger SOD1. </P><P><B><I>Methods and Results</I></B>—Wild-type (WT) and superoxide dismutase 1 (SOD1) overexpressing embryos from nondiabetic WT control dams and nondiabetic/diabetic WT female mice mated with SOD1 transgenic male mice were analyzed. No heart defects were observed in WT and SOD1 embryos under nondiabetic conditions. WT embryos of diabetic dams had a 26% incidence of cardiac outlet defects that were suppressed by SOD1 overexpression. Insulin treatment reduced blood glucose levels and heart defects. Diabetes increased superoxide production, canonical Wnt antagonist expression, caspase activation, and apoptosis, and suppressed cell proliferation. Diabetes suppressed Wnt signaling intermediates and Wnt target gene expression in the embryonic heart, each of which were reversed by SOD1 overexpression. Hydrogen peroxide and peroxynitrite mimicked the inhibitory effect of high glucose on Wnt signaling, which was abolished by the SOD1 mimetic, tempol. </P><P><B><I>Conclusions</I></B>—The oxidative stress of diabetes impairs Wnt signaling and causes cardiac outlet defects that are rescued by SOD1 overexpression. This suggests that targeting of components of the Wnt5a signaling pathway may be a viable strategy for suppression of CHDs in fetuses of diabetic pregnancies.</P> 1 1 0 6 7 no yes CircGenetics_CIRCCVG-2015-001138-T.xml CircGenetics_CIRCCVG-2015-001138-T_file1.doc

CircGenetics_CIRCCVG-2015-001138-T_fig1.ppt

CircGenetics_CIRCCVG-2015-001138-T_supp1.pdf CircGenetics_CIRCCVG-2015-001138-T_supp2.docx CircGenetics_CIRCCVG-2015-001138-T_supp3.pdf CircGenetics_CIRCCVG-2015-001138-T_merge.pdf CircGenetics_CIRCCVG-2015-001138-T_Zhong_272008_disclosure.pdf CircGenetics_CIRCCVG-2015-001138-T_Zhong_272008_copyright.pdf CircGenetics_CIRCCVG-2015-001138-T_Wu_268821_disclosure.pdf CircGenetics_CIRCCVG-2015-001138-T_Wu_268821_copyright.pdf CircGenetics_CIRCCVG-2015-001138-T_Wang_268820_disclosure.pdf CircGenetics_CIRCCVG-2015-001138-T_Wang_268820_copyright.pdf CircGenetics_CIRCCVG-2015-001138-T_Yang_198410_disclosure.pdf CircGenetics_CIRCCVG-2015-001138-T_Yang_198410_copyright.pdf CircGenetics_CIRCCVG-2015-001138-T_Fisher_35108_disclosure.pdf CircGenetics_CIRCCVG-2015-001138-T_Fisher_35108_copyright.pdf Bill authors $70 per pg.; no excess pgs. Article has supplemental material (1 PDF) and a clinical perspective. Rec'd 2/19/14 (Invited from Circulation/De Novo on Circulation) Subject Codes: [130] Animal models of human disease [131] Apoptosis [189] Type 1 diabetes ksine