花生四烯酸的环氧化代谢变异对动脉粥样硬化斑块部位血管收缩及病理进程的调控和分子机制

项目名称： 花生四烯酸的环氧化代谢变异对动脉粥样硬化斑块部位血管收缩及病理进程的调控和分子机制

项目编号： No.81470572

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 周应毕

作者单位： 汕头大学

项目金额： 73万元

中文摘要： 花生四烯酸环氧化代谢在血管收缩功能调节中起重要作用。近来研究表明，在正常血管组织该类反应主要由在内皮细胞表达的一型环氧化酶催化完成、并产生PGI2,后者可激活功能相反的IP和TP受体，分别诱发舒张或血管收缩活动。然在疾病血管，花生四烯酸环氧化代谢途径及作用尚待明确。根据前期实验结果和相关文献报道，我们认为，在动脉粥样硬化斑块部位二型环氧化酶特异性表达上调，产生非PGI2类产物如TxA2和PGE2等，导致内皮依赖性血管收缩活动、及内皮素A型受体等平滑肌受体诱发的收缩反应增强。本项目将围绕此一假说，通过基因敲除小鼠模型和人体血管，结合生理、病理生理及生物化学方法，针对动脉粥样硬化斑块部位的内皮及平滑肌的花生四烯酸环氧化代谢改变、及其对病变血管收缩功能及病理进程的调控作用和分子机制进行研究。预期结果将对动脉粥样硬化病变血管收缩功能及病理调控机制提出新的观点，从而为该病的防治提供新的靶点信息。

中文关键词： 环氧化酶；动脉粥样硬化；前列腺素类；TP受体；EP-3受体

英文摘要： Cyclooygenase-mediated metabolism of arachidonic acid plays an important role in the regulation of vascular contraction. Recent studies have shown that in normal vasculature, this reaction is catalyzed by cyclooxygenase-1 in vascular endothelium,producing PGI2 that activates the functionally opposing IP and TP receptors，which mediate vasodilator or constrictor activity, respectively. However in vascular disease, the role and pathway of such reaction still remain to be elucidated clearly. Base on our preliminary results and those of previously reported, we propose that in vessel areas with atherosclerotic plaques cyclooxygenase-2 is selectively up-regulated and it produces non-PGI2 prostanoids, such as TxA2 and PGE2, which can lead to an increase in the endothelium-derived vasoconstrictor activity and an enhanced reaction to the activation of smooth muscle receptors, such as endothelin type-A receptor. In this project we will center on this hypothesis,using knockout mouse models and human blood vessels in combining with physiological, pathophysiological and biochemical methods to study the underlying mechanisms for the altered cylooxygense pathway of arachidonic acid metabolism, and its role in regulating the pathological process and constrictor activity of vessels with atherosclerotic lesions. Results from this project are expected to yield novel mechanistic insights into the regulation of vessels constriction and pathological processes in vessels with atherosclerosis, hence providing new targeting information for the prevention and treatment of the disorder.

英文关键词： Cyclooxygenase;Atherosclerosis;Prostanoids;TP receptor;EP-3 receptor