Heightened hypoxia and DNA methylation in heart defects of diabetic embryopathy

糖尿病胚胎病心脏缺陷中缺氧和 DNA 甲基化加剧

基本信息

批准号：
10518982
负责人：
Wei-Bin Shen
金额：
$ 75.9万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518982
关键词：
Apoptosis Binding Cardiac Cardiac Myocytes Cell Proliferation Cells Cellular Stress Complex Congenital Abnormality Congenital Heart Defects DNA DNA Methylation DNA Modification Methylases DNA methylation profiling DNMT3B gene DNMT3a Defect Development Diabetes Mellitus Embryo Embryonic Heart Epigenetic Process Exposure to Fetal health Frequencies Functional disorder Gene Expression Genes HCN4 gene Heart Heart Abnormalities Human Hyperglycemia Hypermethylation Hyperoxia Hypertrophy Hypoplastic Left Heart Syndrome Hypoxia Impairment Incidence Inflammation Mus Myocardial dysfunction Pathway interactions Patients Pregnancy in Diabetics Regulatory Element Rodent Model Role Testing Up-Regulation Woman cardiogenesis diabetic diabetic embryopathy epigenetic memory gestational hypoxia glycemic control heart function human disease hypoxia inducible factor 1 imprint improved induced pluripotent stem cell inhibitor insight maternal diabetes non-genetic offspring prevent progenitor programs promoter stem cell differentiation

项目摘要

Summary Maternal diabetes induces congenial heart defects (CHDs) formation and the underlying mechanism is still unclear. Maternal diabetes induces hypoxia in the developing embryo and short-term gestational hypoxia induces CHDs. Hypoxia and DNA hypermethylation have been interlinked in human diseases. DNA hypermethylation is implicated in CHDs including hypoplastic left heart syndrome (HLHS), a complex and severe CHD type. We found that maternal diabetes enhanced hypoxia and increased DNA methylation in the developing heart. Hypoxia inducible factor 1 alpha (HIF-1α) up-regulated the two de novo DNA methyltransferase (DNMT3a and DNMT3b) in cardiac progenitors in the developing mouse hearts or derived from human inducible pluripotent stem cells (iPSCs). Blockage of DNA hypermethylation by removing DNMT3a and DNMT3b in early cardiac Nkx2.5+ progenitors ameliorated all CHD types in diabetic pregnancy. Thus, we hypothesize that maternal diabetes induces hypoxia and triggers the activation of the hypoxia inducible factor 1 alpha (HIF-1α) pathway, which induces DNA hypermethylation by up-regulating DNMT3a/b. Inhibition of hypoxia, HIF-1α or DNA hypermethylation or double DNMT3a/b deletion abrogates the functional deficits in cardiac progenitors leading to CHD reduction and improvement of cardiomyocyte and cardiac function. First heart field defects contribute to HLHS formation and cardiac dysfunction in this severe type of CHDs. To test our hypothesis, we proposed three specific aims. Aim 1 will determine whether maternal diabetes-induced hypoxia is responsible for DNA hypermethylation in early cardiac progenitors leading to CHD formation. We will examine whether hypoxia increases DNA methylation in early cardiac progenitors by up-regulating DNMT3a/b expression leading to CHDs in diabetic pregnancy. Aim 2 will investigate the role of maternal diabetes-induced DNA hypermethylation in gene dysregulation that results in functional defects in early cardiac progenitors and the first heart field. We will determine whether DNA hypermethylation in both heart fields alters gene expression leading to CHDs and cardiomyocyte dysfunction in diabetic pregnancy by using DNMT3a/b double deletion in early cardiac progenitors. Aim 3 will determine whether heightened HIF-1α activity and consequent DNA hypermethylation contribute to cardiomyocyte dysfunction of HLHS in diabetic pregnancy. We hypothesize that persistent activation of the HIF-1α pathway and DNA hypermethylation contribute to cardiomyocyte dysfunction in maternal diabetes-induced CHDs. Successful completion will dissect the critical role of hypoxia and DNA methylation in diabetes-induced CHDs and provide mechanistic insights for improving cardiomyocyte function in CHD patients.

概括孕产妇糖尿病诱发先天性心脏病（CHD）形成，其机制仍不清楚目前尚不清楚，母亲糖尿病会导致发育中的胚胎缺氧，而妊娠期短期缺氧会导致这种情况。缺氧和 DNA 高甲基化在人类疾病中是相互关联的。与冠心病有关，包括左心发育不全综合征（HLHS），这是一种复杂而严重的冠心病类型。母亲的糖尿病会加剧缺氧并增加发育中心脏的 DNA 甲基化。诱导因子 1 α (HIF-1α) 上调两种 DNA 甲基转移酶（DNMT3a 和 DNMT3b）在发育中的小鼠心脏的心脏祖细胞中或源自人类诱导多能干细胞 (iPSC) 通过去除早期心脏 Nkx2.5+ 中的 DNMT3a 和 DNMT3b 来阻断 DNA 高甲基化。祖细胞改善了糖尿病妊娠中所有类型的先心病，因此，我们与母亲糖尿病作斗争。诱导缺氧并触发缺氧诱导因子 1 α (HIF-1α) 通路的激活，通过上调 DNMT3a/b 抑制缺氧、HIF-1α 或 DNA 来诱导 DNA 高甲基化。高甲基化或双重 DNMT3a/b 缺失消除了心脏祖细胞的功能缺陷导致冠心病的减少和心肌细胞和心脏功能的改善。缺陷会导致这种严重类型的先心病中 HLHS 的形成和心脏功能障碍。假设，我们提出了三个具体目标目的1 将确定母亲是否诱发糖尿病。缺氧导致早期心脏祖细胞 DNA 高甲基化，导致冠心病 (CHD) 形成。我们将检查缺氧是否通过上调来增加早期心脏祖细胞中的 DNA 甲基化 DNMT3a/b 表达导致糖尿病妊娠中的冠心病 (CHD) 目标 2 将研究母体的作用。糖尿病引起的基因失调中的 DNA 高甲基化导致早期功能缺陷我们将确定两个心脏中的DNA是否高甲基化。通过使用磁场改变基因表达，导致糖尿病妊娠中的冠心病和心肌细胞功能障碍早期心脏祖细胞中的 DNMT3a/b 双缺失将决定是否呼吸 HIF-1α。 HLHS 活性和随之而来的 DNA 高甲基化导致 HLHS 心肌细胞功能障碍我们与 HIF-1α 通路的持续激活和 DNA 高甲基化作斗争。成功完成将剖析母亲糖尿病引起的心肌细胞功能障碍。缺氧和 DNA 甲基化在糖尿病引起的先心病中的关键作用，并提供机制见解改善冠心病患者的心肌细胞功能。