前列腺素I和E在血管再狭窄中的基础研究与应用

Prostanoids are bioactive lipids derived from arachidonic acid (AA), which is released from membrane phospholipids upon stimulation. AA is initially catalyzed by cyclooxygenase(COX) to form an intermediate product, which is then converted to form individual protanoids by corresponding terminal prostaglandin synthases. Prostanoids exhibit extensive regulatory role in cardiovascular function, including the cardiovascular protection of aspirin, which is mediated by suppression of platelet cyclooxygenase(COX)-1 derived thromboxane. Clinical trials consistently show that increased cardiovascular hazard is associated with COX-2 selective inhibitors, which is attributable to the suppression of prostaglandin (PG) I, also known as prostacyclin. This has shifted interest in therapeutic target selection to downstream prostanoid synthase. The applicant's previous work demonstrates that deletion of microsomal(m) PGE synthase(S)-1, in contrast to COX-2 selective inhibition, does not increase thrombosis risk. Further, mPGES-1 deletion, reduces PGE levels, retards atherogenesis and injury-induced vascular remodeling. These vascular beneficial effects are attributable to the documented increase in PGI formation. However, the role of PGI upregulation and PGE reduction in mediating the vascular remodeling is unclear. It is hypothesized that both PGI and PGE regulate development of restenosis, a vascular remodeling process that leads to occlusion of arterial lumen. It is aimed to (1) clarify the relative contribution of platelet inhibition vs endothelial repair in mediating the protective role of PGI receptor (IP) against restenosis; (2) delineate the role of PGE suppression while sparing PGI signaling, in mediating the attenuated neointimal formation resulted from mPGES-1 deletion; and explore therapeutic potential of pharmacological intervention for vascular restenosis by inhibiting endogenous PGE and harnessing PGI analogue; (3) establish clinical detection of PGI and PGE (metabolites) and explore the relation of PGI and PGE with development of restenosis. This study elucidates mechanisms of action of individual prostaglandins in cardiovascular function, and may provide opportunities for clinical application and therapeutic discovery for vascular restenosis.

前列腺素类分子具有广泛的心血管调节作用。例如阿司匹林通过抑制前列腺素合成途径上的环氧合酶-1起心血管保护作用，相反，抑制环氧合酶-2已经被临床试验证明增加心血管不良事件风险，而这归因于对于前列环素(PGI)的抑制。申请人发表的动物研究表明敲除前列腺素E合成酶-1(mPGES-1)可以抑制机械损伤诱导的血管重构的发生，这与升高PGI和抑制PGE有关。本研究设想PGI和PGE共同调节血管再狭窄形成，在整体水平上，PGI抑制而PGE促进血管再狭窄形成。本研究目的是(1)澄清PGI是否通过对血小板抑制和内皮修复的影响来抑制血管再狭窄；(2)确定PGI上调在介导mPGES-1敲除对血管再狭窄抑制中的作用，探索PGI类似物和mPGES-1药理学抑制对血管再狭窄的作用；(3)临床检测确定PGI与PGE与血管再狭窄发生的关系。本研究具有探索血管再狭窄病变机制的理论价值和临床预后及治疗的潜在应用价值。

环氧合酶COX-1及COX-2是前列腺素类分子合成的关键酶。COX-1及COX-2抑制剂已被广范用于临床治疗炎症、疼痛及发热等疾病。但此类药物存在心血管副反应。COX-2抑制剂已经被临床试验证明增加心血管不良事件风险。抑制环氧合酶下游的前列腺素E（PGE2）合成酶mPGES-1，升高PGI2,具有心血管保护作用，因此mPGES-1成为潜在的替代环氧合酶的重要靶点。但目前对mPGES-1的心血管作用研究并不清晰。本项目直接澄清了mPGES-1及其来源的PGE2在血管重构及心脏缺血再灌注中的作用，并探究了其作用机制。结果显示，mPGES-1-PGE2,不依赖于PGI2的参与，对血管重构及心脏缺血再灌注损伤均具有保护作用。且内皮细胞EP4受体是其发挥保护性作用的关键受体。本部分研究对全面认识潜在药靶mPGES-1的心血管作用具有重要意义。对临床选择使用前列腺素通路抑制剂的时机及心血管风险预测具有重要的参考价值。.在本项目执行的过程中，发现了与PGE相关的另一个趋化因子受体（CXCR7）信号通路可能参与血管重构。并在另一项自然基金委项目的共同支持下，开展了CXCR7在血管重构与心梗中的作用与机制研究。趋化因子CXCL12，同前列腺素类物质类似，为体内炎症反应调节分子。其具有两型受体，CXCR4和CXCR7。CXCR4为CXCL12的经典受体，介导细胞迁移，并在心血管系统中介导保护性作用。CXCR7是近来发现的CXCL12受体，其对CXCL12的侵和力更强。但CXCR7在心血管系统中的作用如何，并不清楚。本项目对CXCR7的心血管作用进行了探索。结果显示，CXCR7通过促进内皮细胞增殖与成管，在血管再狭窄及心梗后心脏重构中发挥保护作用。本部分研究证实CXCR7是内皮细胞调节血管稳态，进而影响心梗后心功能及心脏重构的一种新的调节机制。这进一步突出了内皮细胞在心梗治疗中的重要性。也为药物开发提供了具有潜力的新型药靶。.综上所述，本项目通过对传统及新型炎症调节分子作用通路的研究，澄清了热点药靶mPGES-1的心血管作用并阐明了其机制，同时发现并深入研究了CXCR7的重要心血管保护作用。本研究在药靶研究及药靶发现上，做出了具有原创性地贡献。也为临床用药及研究提供了一定的参考。

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