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

描述（由申请人提供）：前列腺素类，包括前列腺素E2（PGE 2），与许多心血管疾病的病理生理学有关。初步数据表明，选择性药理学抑制环氧合酶-2（考克斯-2）可显著降低血管紧张素II（AngII）输注小鼠腹主动脉瘤（AAA）的发病率，表明前列腺素类在AAA的发生中起关键作用。AAA形成的标志是炎症和血管壁中基质金属蛋白酶（MMPs）的表达和活化增加。在炎症过程中，考克斯-2和微粒体前列腺素E合酶-1（m-PGES-1）均快速上调，导致PGE 2浓度增加。PGE 2调节MMP表达和活化，因此考克斯-2产生的PGE 2的减少可能导致MMP表达和活化的减少。先前的研究已经将PGE 2的减少与MMPs的减少和子宫内膜扩张相关联。初步数据表明，m-PGES 1缺陷减弱AngII诱导的AAA形成。在mPGES-1缺陷小鼠中，PGE 2浓度显著降低，然而，前列环素（PGI 2）浓度随之增加。PGI 2受体的阻断可防止其他血管疾病的发展。因此，PGE 2在介导AAAs发展中的直接作用尚未阐明。PGE 2通过结合EP受体介导其作用。EP 4受体在平滑肌组织中表达，并且是激活MMPs所必需的。本提案的长期目标是阐明PGE 2在AngII诱导的AAA形成中的作用。我们建议测试的假设，mPGES-1产生的PGE 2介导的初始阶段的血管紧张素II诱导的AAA的形成通过EP 4受体。为了验证这一假设，我们建议：1）确定mPGES-1产生的PGE 2在AngII诱导的AAA中的作用; 2）确定PGE 2-EP 4受体轴在涉及AAA发展的细胞中MMP表达和活化中的作用; 3）确定EP 4受体是否对AngII诱导的AAA的发展至关重要。到目前为止，还没有针对AAA的治疗方法。由于心血管事件风险增加是考克斯-2抑制剂的一类特异性效应，这些研究的数据对于确定考克斯-2产生的哪些前列腺素类介导AAA形成的初始事件非常重要，并为我们提供了靶向特定前列腺素类糖苷酶和受体作为该疾病治疗方法的关键信息。

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.