20-HETE在非甾体抗炎药致心血管损伤中的作用及机制研究

项目名称： 20-HETE在非甾体抗炎药致心血管损伤中的作用及机制研究

项目编号： No.81470588

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： 刘俊彦

作者单位： 同济大学

项目金额： 68万元

中文摘要： 非甾体抗炎药（NSAIDs）是风湿病患者长期服用的常见药物。已知非阿司匹林类NSAIDs均增加心血管疾病风险，但其致心血管损伤机制不清。前期我们发现：（1）罗非昔布导致小鼠血浆20-HETE和sP-selectin显著升高；（2）20-HETE显著缩短小鼠尾部流血时间；(3) 20-HETE时间和剂量依赖性地促血小板聚集。因sP-selectin是血小板活化标志物，且NSAIDs能引起血小板功能紊乱和内皮细胞功能障碍，故我们认为：由NSAIDs引起的血液20-HETE增高参与激活血小板功能紊乱和内皮细胞功能障碍是其增加心血管疾病风险的重要机制。为此，本项目首先确定非阿司匹林类NSAIDs致20-HETE浓度升高及其与血小板和内皮功能障碍的关系；随后阐明20-HETE损伤血小板和内皮细胞功能的分子机制；最后采用临床样本加以验证。本项目的实施有望为预防NSAIDs致心血管损伤提供新的干预靶点。

中文关键词： 非甾体抗炎药；代谢组学；心血管；血小板功能紊乱；内皮功能障碍

英文摘要： Non-steroidal anti-inflammatory drugs (NSAIDs) are the common drugs clinically used for the chronic treatment of arthritis. Non-aspirin NSAIDs have all been found to be associated with the increased risks in cardiovascular diseases such as hypertension, myocardial infarct, and stroke. However, the meachanisms underlying NSAIDs-mediated cardiovascular events have not be understood completely. We previously found that (1) chronic administration of rofecoxib resulted in significant increase in plasma level of both 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoconstrictor, and sP-selectin, the biomarker of platelet activation; (2) 20-HETE shortened the tail bleeding time significantly in a murine model; (3) 20-HETE accelerated rodent platelet aggregation time- and dose-dependently. Some NSAIDs have been known to be associated with platelet function disorder and endothelial dysfunction, therefore, we hypothesize that increased circulation level of 20-HETE caused by chronic administration of NSAIDs is involved in the activation of platelet function disorder and endothelial dysfunction, which is the general reason for the NSIADs-mediated cardiovascular events. To test above hypothesis, we propose to investigate the dose- and time-dependent changes in plasma level of 20-HETE caused by NSAIDs administration, which will be correlated to the dose- and time-dependent changes in blood coagulation system (e.g. blood bleeding time, and particular the key biomarkers of platelet function such as sP-selectin, fibrinogen, cAMP, thrombin, t-PA and PAI-1 and key biomarkers of endothelial function such as ICAM-1, VCAM-1, MCP-1 and ADMA) in a animal model. We will further test the dose- and time-dependent effect of 20-HETE on the blood coagulation system by using both an in vitro and an in vivo models. We will finally test the foundings from above studies in associated clinical samples. By correlating the changes in 20-HETE, coagulation biomarkers, and the key signaling pathways, this proposal will bring a comprehensive understanding of the mechanism underlying NSAIDs-mediated cardiovascular events. Based on our findings, novel strategies will be proposed to prevent the risks of cardiovascular events caused by the administration of NSAIDs, creating a safer translational medication.

英文关键词： Nonsteroidal antiinflammatory drugs;metabolomics;cardiovascular;platelet function disorder;endothelial dysfunction