The role of Prostaglandin E2 in Angiotensin II-induced vascular disease

描述(由申请人提供)：前列腺素E_2(PGE_2)等前列腺素类药物与许多心血管疾病的病理生理学有关。初步研究表明，选择性抑制环氧合酶-2(COX-2)可显著降低血管紧张素II(AngII)注射小鼠腹主动脉瘤(AAA)的发生率，提示前列腺素在AAA的发生发展中起重要作用。AAA形成的特征是炎症和血管壁中基质金属蛋白酶(MMPs)的表达和激活增加。在炎症过程中，COX-2和微粒体前列腺素E合成酶-1(m-PGES-1)迅速上调，导致PGE2浓度升高。前列腺素E_2调节基质金属蛋白酶的表达和活化，因此COX-2产生的前列腺素E_2的减少可能导致基质金属蛋白酶的表达和活化减少。以前的研究已经将PGE2的减少与MMPs的减少和动脉瘤的扩大联系在一起。初步数据显示，m-PGES1缺乏可减弱血管紧张素Ⅱ诱导的AAA的形成。MPGES-1基因缺陷小鼠的前列腺素E_2浓度显著降低，而前列环素(PGI_2)浓度却随之升高。阻断PGI2受体可以防止其他血管疾病的发展。因此，PGE2在AAAs发病过程中的直接作用尚未阐明。PGE2通过与EP受体结合来介导其作用。EP4受体在动脉瘤组织中表达，是激活MMPs所必需的。这项建议的长期目标是阐明PGE2在血管紧张素转换酶诱导的AAA形成中的作用。我们建议检验这一假设，即mPGES-1产生的PGE2通过EP4受体介导Angii诱导的AAA形成的初始阶段。为了验证这一假说，我们建议：1)确定mPGES-1产生的PGE2在Angii诱导的AAA中的作用；2)确定PGE2-Ep4受体轴在参与AAA发生的细胞中的MMP表达和激活中的作用；3)确定Ep4受体是否在Angii诱导的AAA的发展中起关键作用。到目前为止，还没有治疗AAA的方法。鉴于心血管事件风险的增加是COX-2抑制剂的一种特殊作用，这些研究的数据将对确定由COX-2产生的哪些前列腺素类物质介导AAA形成的初始事件并为靶向特定的前列腺素合成酶和受体作为治疗该疾病的治疗提供关键信息。

DESCRIPTION (provided by applicant): Prostanoids, including prostaglandin E2 (PGE2), have been implicated in the pathophysiology of a number of cardiovascular diseases. Preliminary data demonstrates that selective pharmacological inhibition of cyclooxygenase-2 (COX-2) markedly attenuates the incidence of abdominal aortic aneurysms (AAA) in mice infused with angiotensin II (AngII), suggesting that prostanoids play a critical role in the development of AAAs. Hallmarks of AAA formation are inflammation and increased expression and activation of matrix metalloproteinases (MMPs) in the vascular wall. During inflammation both COX-2 and microsomal prostaglandin E synthase-1 (m-PGES-1) are rapidly upregulated resulting in increased concentrations of PGE2. PGE2 regulates MMP expression and activation, therefore reductions in COX-2 generated PGE2 may result in decreases in MMP expression and activation. Previous studies have associated reductions in PGE2 with decreases in MMPs and aneurysmal expansion. Preliminary data demonstrates that m-PGES1 deficiency attenuates AngII-induced AAA formation. PGE2 concentrations were markedly decreased in the mPGES-1 deficient mice, however, there was a concomitant increase in prostacyclin (PGI2) concentrations. Blockade of the PGI2 receptor protects against that development of other vascular disease. Therefore, the direct role of PGE2 in mediating the development of AAAs has not been elucidated. PGE2 mediates its actions by binding to EP receptors. The EP4 receptor is expressed in aneurysmal tissues and is required for the activation MMPs. The long-term objective of this proposal is to elucidate the role of the PGE2 in AngII-induced AAA formation. We propose to test the hypothesis that mPGES-1 generated PGE2 mediates the initial stage of AngII-induced AAA formation via the EP4 receptor. To test this hypothesis we propose to: 1) define the role of mPGES-1 generated PGE2 in AngII-induced AAAs; 2) define the role of the PGE2-EP4 receptor axis in MMP expression and activation in cells implicated in the development of AAAs and; 3) determine if the EP4 receptor is critical for the development of AngII-induced AAAs. To date there are not therapeutic treatments for AAAs. With the suggestion that an increased risk for cardiovascular events is a class specific effect of COX-2 inhibitors, data from these studies will be important in defining which prostanoids generated by COX-2 mediate the initial events in AAA formation and provide us with critical information for targeting specific prostanoid synthases and receptors as therapeutic treatment for this disease.