Fang Wang1, E Albert Reece2, Peixin Yang3. 1. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD. 2. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD. 3. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD. Electronic address: pyang@fpi.umaryland.edu.
Abstract
OBJECTIVE: Oxidative stress plays a causal role in diabetic embryopathy. Maternal diabetes induces heart defects and impaired transforming growth factor beta (TGFβ) signaling, which is essential for cardiogenesis. We hypothesize that mitigating oxidative stress through superoxide dismutase 1 (SOD1) overexpression in transgenic (Tg) mice reverses maternal hyperglycemia-impaired TGFβ signaling and its downstream effectors. STUDY DESIGN: Day 12.5 embryonic hearts from wild-type (WT) and SOD1 overexpressing embryos of nondiabetic (ND) and diabetic mellitus (DM) dams were used for the detection of oxidative stress markers: 4-hydroxynonenal (4-HNE) and malondlaldehyde (MDA), and TGFβ1, 2, and 3, phosphor (p)-TGFβ receptor II (TβRII), p-phosphorylated mothers against decapentaplegic (Smad)2, and p-Smad3. The expression of 3 TGFβ-responsive genes was also assessed. Day 11.5 embryonic hearts were explanted and cultured ex vivo, with or without treatments of a SOD1 mimetic (Tempol; Enzo Life Science, Farmingdale, NY) or a TGFβ recombinant protein for the detection of TGFβ signaling intermediates. RESULTS: Levels of 4-HNE and MDA were significantly increased by maternal diabetes, and SOD1 overexpression blocked the increase of these 2 oxidative stress markers. Maternal diabetes suppresses the TGFβ signaling pathway by down-regulating TGFβ1 and TGFβ3 expression. Consequently, phosphorylation of TβRII, Smad2, and Smad3, downstream effectors of TGFβ, and expression of 3 TGFβ-responsive genes were reduced by maternal diabetes, and these reductions were prevented by SOD1 overexpression. Treatment with Tempol or TGFβ recombinant protein restored high-glucose-suppressed TGFβ signaling intermediates and responsive gene expression. CONCLUSION: Oxidative stress mediates the inhibitory effect of hyperglycemia in the developing heart. Antioxidants, TGFβ recombinant proteins, or TGFβ agonists may have potential therapeutic values in the prevention of heart defects in diabetic pregnancies.
OBJECTIVE: Oxidative stress plays a causal role in diabetic embryopathy. Maternal diabetes induces heart defects and impaired transforming growth factor beta (TGFβ) signaling, which is essential for cardiogenesis. We hypothesize that mitigating oxidative stress through superoxide dismutase 1 (SOD1) overexpression in transgenic (Tg) mice reverses maternal hyperglycemia-impaired TGFβ signaling and its downstream effectors. STUDY DESIGN: Day 12.5 embryonic hearts from wild-type (WT) and SOD1 overexpressing embryos of nondiabetic (ND) and diabetic mellitus (DM) dams were used for the detection of oxidative stress markers: 4-hydroxynonenal (4-HNE) and malondlaldehyde (MDA), and TGFβ1, 2, and 3, phosphor (p)-TGFβ receptor II (TβRII), p-phosphorylated mothers against decapentaplegic (Smad)2, and p-Smad3. The expression of 3 TGFβ-responsive genes was also assessed. Day 11.5 embryonic hearts were explanted and cultured ex vivo, with or without treatments of a SOD1 mimetic (Tempol; Enzo Life Science, Farmingdale, NY) or a TGFβ recombinant protein for the detection of TGFβ signaling intermediates. RESULTS: Levels of 4-HNE and MDA were significantly increased by maternal diabetes, and SOD1 overexpression blocked the increase of these 2 oxidative stress markers. Maternal diabetes suppresses the TGFβ signaling pathway by down-regulating TGFβ1 and TGFβ3 expression. Consequently, phosphorylation of TβRII, Smad2, and Smad3, downstream effectors of TGFβ, and expression of 3 TGFβ-responsive genes were reduced by maternal diabetes, and these reductions were prevented by SOD1 overexpression. Treatment with Tempol or TGFβ recombinant protein restored high-glucose-suppressed TGFβ signaling intermediates and responsive gene expression. CONCLUSION: Oxidative stress mediates the inhibitory effect of hyperglycemia in the developing heart. Antioxidants, TGFβ recombinant proteins, or TGFβ agonists may have potential therapeutic values in the prevention of heart defects in diabetic pregnancies.
Authors: Suzanne M Gilboa; Adolfo Correa; Lorenzo D Botto; Sonja A Rasmussen; D Kim Waller; Charlotte A Hobbs; Mario A Cleves; Tiffany J Riehle-Colarusso Journal: Am J Obstet Gynecol Date: 2009-10-01 Impact factor: 8.661
Authors: Z J Hagay; Y Weiss; I Zusman; M Peled-Kamar; E A Reece; U J Eriksson; Y Groner Journal: Am J Obstet Gynecol Date: 1995-10 Impact factor: 8.661
Authors: L P Sanford; I Ormsby; A C Gittenberger-de Groot; H Sariola; R Friedman; G P Boivin; E L Cardell; T Doetschman Journal: Development Date: 1997-07 Impact factor: 6.868
Authors: Daoyin Dong; Yuji Zhang; E Albert Reece; Lei Wang; Christopher R Harman; Peixin Yang Journal: Reprod Toxicol Date: 2016-09-11 Impact factor: 3.143
Authors: Yanqing Wu; E Albert Reece; Jianxiang Zhong; Daoyin Dong; Wei-Bin Shen; Christopher R Harman; Peixin Yang Journal: Am J Obstet Gynecol Date: 2016-03-31 Impact factor: 8.661