Oxidative stress is responsible for maternal diabetes-impaired transforming growth factor beta signaling in the developing mouse heart.
Oxidative stress is responsible for maternal diabetes-impaired transforming growth factor beta signaling in the developing mouse heart.
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DOI：
10.1016/j.ajog.2015.01.014
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发表时间：
2015-05
影响因子：
9.8
通讯作者：
Yang, Peixin
中科院分区：
文献类型：
--
作者：
Wang, Fang;Reece, Albert;Yang, Peixin
关键词：
氧化应激在糖尿病胚胎病中起着重要作用。母体糖尿病可诱导心脏缺陷和受损的转化生长因子β（TGFβ）信号传导，这对心脏发生至关重要。我们假设，通过超氧化物歧化酶1（SOD 1）过表达减轻氧化应激在转基因（Tg）小鼠逆转母体高血糖受损的TGFβ信号及其下游效应。将来自非糖尿病（ND）和糖尿病（DM）母鼠的野生型（WT）和SOD 1过表达胚胎的12.5天胚胎心脏用于检测氧化应激标志物：4-羟基壬烯醛（4-HNE）和丙二醛（MDA），以及TGFβ1，2，3，磷（p）-TGFβ受体II（TβRII），p-Smad 2和p-Smad 3。还评估了三种TGFβ应答基因的表达。将第11.5天的胚胎心脏体外培养，用或不用SOD 1模拟物（tempol）或TGFβ重组蛋白处理，以检测TGFβ信号传导中间体。4-HNE和MDA水平显着增加，母亲糖尿病，和SOD 1过表达阻断这两个氧化应激标志物的增加。母体糖尿病通过下调TGFβ1和TGFβ3的表达来抑制TGFβ信号通路。因此，TGFβ下游效应因子TβRII、Smad 2和Smad 3的磷酸化以及三种TGFβ反应基因的表达均因母体糖尿病而降低，而这些降低可被SOD 1过表达所阻止。用tempol或TGFβ重组蛋白治疗恢复了高糖抑制的TGFβ信号传导中间体和响应性基因表达。氧化应激介导高血糖对发育中心脏的抑制作用。抗氧化剂、TGFβ重组蛋白或TGFβ激动剂可能对预防糖尿病妊娠心脏缺陷具有潜在的治疗价值。
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. Day 12.5 embryonic hearts from wild-type (WT) and SOD1 overexpressing embryos of nondiabetic (ND) and diabetic mellitus (DM) dams were used for detection of oxidative stress markers: 4-hydroxynonenal (4-HNE) and malondlaldehyde (MDA), and TGFβ1, 2, 3, phosphor (p)-TGFβ receptor II (TβRII), p-Smad2 and p-Smad3. The expression of three 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) or a TGFβ recombinant protein for detection of TGFβ signaling intermediates. Levels of 4-HNE and MDA were significantly increased by maternal diabetes, and SOD1 overexpression blocked the increase of these two 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 three 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. 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.
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影响因子：
20.1
作者：
Compton, Leigh A.;Potash, Dru A.;Barnett, Joey V.
通讯作者：
Barnett, Joey V.
影响因子：
9.8
作者：
Correa, Adolfo;Gilboa, Suzanne M.;Reece, E. Albert
通讯作者：
Reece, E. Albert
影响因子：
4.5
作者：
Badr G;Mahmoud MH;Farhat K;Waly H;Al-Abdin OZ;Rabah DM
通讯作者：
Rabah DM
影响因子：
9.8
作者：
Gilboa, Suzanne M.;Correa, Adolfo;Riehle-Colarusso, Tiffany J.
通讯作者：
Riehle-Colarusso, Tiffany J.
在怀孕和早产期间重复测量尿氧化应激生物标志物。
影响因子：
9.8
作者：
Ferguson, Kelly K.;McElrath, Thomas F.;Chen, Yin-Hsiu;Loch-Caruso, Rita;Mukherjee, Bhramar;Meeker, John D.
通讯作者：
Meeker, John D.