Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart.
Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart.
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DOI：
10.1186/s12933-018-0713-0
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发表时间：
2018-05-12
影响因子：
9.3
通讯作者：
Pavlinkova G
中科院分区：
文献类型：
--
作者：
Cerychova R;Bohuslavova R;Papousek F;Sedmera D;Abaffy P;Benes V;Kolar F;Pavlinkova G
流行病学研究表明，母亲糖尿病易使后代患心血管和代谢紊乱。然而，对潜在的痴呆和疾病易感性的确切机制仍然知之甚少。我们研究了缺氧诱导因子1 α与糖尿病宫内环境的结合是否会影响成年后代心脏的功能和分子结构。在小鼠模型中，我们证明了糖尿病妊娠的单倍不足（Hif 1a +/−）后代在12周龄时发生左心室功能障碍，表现为心肌缩短率降低和结构重塑。通过RNA-seq进行的转录谱分析显示，糖尿病暴露的Hif 1a +/−后代的左心室中存在显著的转录组变化，这些变化与发育、代谢、凋亡和血管生理学相关。相比之下，来自糖尿病妊娠的野生型和Hif 1a +/−后代都表现出免疫系统过程和炎症反应的变化。免疫组化分析表明，Hif 1a单倍不足和暴露于母体糖尿病的组合导致巨噬细胞浸润受损，晚期糖基化终产物水平升高，以及成年后代心脏血管稳态的变化。总之，我们的研究结果提供了证据表明，Hif 1a基因剂量的全球减少增加了暴露于母体糖尿病的后代对心功能障碍的易感性，并强调Hif 1a是成人心血管疾病胎儿编程的关键因素。本文的在线版本（10.1186/s12933-018-0713-0）包含补充材料，可供授权用户使用。
Epidemiological studies show that maternal diabetes predisposes offspring to cardiovascular and metabolic disorders. However, the precise mechanisms for the underlying penetrance and disease predisposition remain poorly understood. We examined whether hypoxia-inducible factor 1 alpha, in combination with exposure to a diabetic intrauterine environment, influences the function and molecular structure of the adult offspring heart. In a mouse model, we demonstrated that haploinsufficient (Hif1a+/−) offspring from a diabetic pregnancy developed left ventricle dysfunction at 12 weeks of age, as manifested by decreased fractional shortening and structural remodeling of the myocardium. Transcriptional profiling by RNA-seq revealed significant transcriptome changes in the left ventricle of diabetes-exposed Hif1a+/− offspring associated with development, metabolism, apoptosis, and blood vessel physiology. In contrast, both wild type and Hif1a+/− offspring from diabetic pregnancies showed changes in immune system processes and inflammatory responses. Immunohistochemical analyses demonstrated that the combination of haploinsufficiency of Hif1a and exposure to maternal diabetes resulted in impaired macrophage infiltration, increased levels of advanced glycation end products, and changes in vascular homeostasis in the adult offspring heart. Together our findings provide evidence that a global reduction in Hif1a gene dosage increases predisposition of the offspring exposed to maternal diabetes to cardiac dysfunction, and also underscore Hif1a as a critical factor in the fetal programming of adult cardiovascular disease. The online version of this article (10.1186/s12933-018-0713-0) contains supplementary material, which is available to authorized users.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
20.1
作者：
BASHEY, RI;MARTINEZHERNANDEZ, A;JIMENEZ, SA
通讯作者：
JIMENEZ, SA
影响因子：
37.8
作者：
Crispi, Fatima;Bijnens, Bart;Gratacos, Eduard
通讯作者：
Gratacos, Eduard
影响因子：
4.8
作者：
Hlatky, Mark A.;Quertermous, Thomas;Go, Alan S.
通讯作者：
Go, Alan S.
影响因子：
4.8
作者：
Gilkes, Daniele M.;Bajpai, Saumendra;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.