The toxin and hypoxia pathways in cardiogenesis

心脏发生中的毒素和缺氧途径

• 批准号: 6855234
• 负责人: MICHIKO WATANABE
• 金额: $ 22.75万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-09 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855234
• 关键词: biological signal transduction; cardiac myocytes; cardiogenesis; cardiotoxin; chick embryo; developmental genetics; dioxins; hypoxia; hypoxia inducible factor 1; oxygen tension; toxin metabolism; transfection

DESCRIPTION (provided by applicant): Competition between the toxin and hypoxia inducible factor responsive (HIF) pathways for a common heterodimer partner Arnt/HIF1b has been demonstrated using in vitro assays and cell culture lines. Evidence is accumulating that these pathways act at critical stages of cardiovascular development including early development of the coronary vasculature. The toxin TCDD, the prototypical agonist for AhR (aryl hydrocarbon receptor) of the toxin pathway, causes abnormal development of the coronary vascular that precedes and may be the basis for TCDD-induced dilated cardiomyopathy. Our findings identify the outflow tract myocardium as the cardiac tissue with the lowest oxygen tension (most hypoxic) at stages and site coincident with cardiomyocyte apoptosis, VEGFR2 expression, nuclear localization of HIF-1a, and accumulation of endothelial precursors of the coronary vasculature. Furthermore, this hypoxia is critical for normal cardiac development. When simultaneously subjected to both stresses, low oxygen tension during normal development and toxin exposure, the molecular and cellular events at this stage and site may be particularly susceptible to competition for signaling molecules such as Arnt/HIF1b resulting in imbalanced gene expression and abnormal development. Our working hypothesis is that activation of the toxin pathway will interfere with normal HIF signaling and HIF-induced gene expression required for cardiogenesis. We will compare the expression of HIF responsive genes with and without TCDD exposure in normally hypoxic cardiac regions of the avian embryo. We will also specifically disrupt HIF signaling by interfering with HIF1a binding in cardiomyocytes in ovo by viral transfection and compare cardiac and coronary vascular phenotypes to that of TCDD-treated embryos. This analysis would be expected to uncover the mechanisms of normal cardiac and coronary vascular development as well as the etiology of cardiotoxicity.

描述（由申请人提供）：已使用体外测定和细胞培养系证明了常见异二聚体伙伴 Arnt/HIF1b 的毒素和缺氧诱导因子反应 (HIF) 途径之间的竞争。越来越多的证据表明，这些途径在心血管发育的关键阶段起作用，包括冠状脉管系统的早期发育。毒素 TCDD 是毒素途径 AhR（芳烃受体）的原型激动剂，会导致冠状血管异常发育，从而导致 TCDD 诱发的扩张型心肌病，并可能是其基础。我们的研究结果将流出道心肌确定为氧张力最低（最缺氧）的心脏组织，其阶段和部位与心肌细胞凋亡、VEGFR2 表达、HIF-1a 的核定位和冠状脉管系统内皮前体的积累一致。此外，这种缺氧对于正常的心脏发育至关重要。当同时承受压力、正常发育过程中的低氧张力和毒素暴露时，该阶段和部位的分子和细胞事件可能特别容易受到信号分子（如 Arnt/HIF1b）的竞争，导致基因表达失衡和发育异常。我们的工作假设是，毒素途径的激活会干扰心脏发生所需的正常 HIF 信号传导和 HIF 诱导的基因表达。我们将比较在正常缺氧的禽类胚胎心脏区域有和没有接触 TCDD 的情况下 HIF 反应基因的表达。我们还将通过病毒转染干扰卵内心肌细胞中 HIF1a 的结合来特异性破坏 HIF 信号传导，并将心脏和冠状血管表型与 TCDD 处理的胚胎进行比较。该分析有望揭示正常心脏和冠状血管发育的机制以及心脏毒性的病因。