十溴联苯醚暴露对血管内皮的损伤及其分子机制研究

Cardiovascular diseases have become the leading cause of death and disability in modern society. Dysfunction of vascular endothelium is one of the critical underlying steps in the initiation and development of such diseases. There is growing evidence that, except for the traditional risk factors, exposure to persistent organic pollutants (POPs) can also lead to severe endothelial injury. Decabromodiphenyl ether (BDE-209) is an emerging POP which presents extensively in human populations; whether this contaminant can induce vascular endothelium dysfunction and the potential mechanisms involved remain not very clear. This proposed study will assess the endothelial injury by BDE-209 exposure, using human aortic endothelial cells and mice as models. We set out to evaluate whether BDE-209 exposure would lead to changes in 1) endothelial adhesion, migration, or angiogenesis; 2) microRNA (miRNA) profiles in endothelium-derived microparticle (EMP) and the protein expression in the direct downstream target cells; and 3) vascular structure and function in mice. The current study will be essential to characterize the cardiovascular toxicity induced by BDE-209, and can offer new strategies for the prevention and treatment of cardiovascular diseases.

心血管病是威胁现代社会人类健康的头号杀手，血管内皮损伤是该类疾病发生发展的关键机制之一。研究发现，除了传统的危险因素，持久性有机污染物（POPs）暴露亦可导致血管内皮损伤。十溴联苯醚（BDE-209）是人体内含量较高的一种新型POPs，这种污染物是否可以损伤血管内皮及其致病机制尚不完全清楚。本项目拟以人主动脉内皮细胞和小鼠为模型，研究BDE-209暴露对血管内皮细胞功能（内皮细胞黏附能力、迁移能力和小管形成能力）的影响、内皮衍生微粒（EMP）中小RNA（miRNA）及下游靶细胞蛋白表达水平的变化和小鼠血管功能的改变，探寻BDE-209暴露对于血管内皮功能的影响及其分子机制。本项目的完成，对于阐明BDE-209的心血管毒性及分子机制具有重要的意义，也为以血管病变为基础的心血管病防治提供新思路。

持久性有机污染物（Persistent Organic Pollutants，POPs）是一类在环境中具有长期残留性、生物蓄积性和高毒性的化学物质。流行病学调查结果显示，心血管病或其危险因素与多种POPs（如二噁英、多氯联苯、多溴联苯醚、全氟化合物和硫丹等）暴露密切相关。十溴联苯醚（BDE-209）是一种新型POPs，因其具有良好的阻燃性能和价格便宜等特点，BDE-209被用作阻燃剂在全球范围内大量使用，是人体中含量较高的一种新型污染物。然而在人体内蓄积量较高的BDE-209的心血管毒性研究尚少。本研究以细胞与小鼠为模型，通过探索BDE-209对于血管内皮细胞与外周血内皮祖细胞的作用，阐明BDE-209暴露对于血管稳态的破坏。研究结果证实，BDE-209暴露可以通过影响血管内皮细胞释放的EMP内的miR-19b的表达，抑制内皮细胞分泌VEGF，进而损伤血管内皮细胞的小管形成能力，抑制其修复受损血管；BDE-209暴露可以促进内皮祖细胞内miR-150的生成，抑制内皮祖细胞表面受体CXCR4的表达，进而损伤血管内皮祖细胞的小管形成能力，减弱其对受损血管的修复；小鼠灌胃实验证实BDE-209暴露可通过抑制内皮联接蛋白的表达，破坏血管内皮的完整性，损伤了血管的收缩与舒张功能，且这种血管毒性呈现时间依赖效应。本项目的完成，对于阐明BDE-209的心血管毒性及分子机制具有重要的意义，也为以血管病变为基础的心血管病防治提供新思路。