PGE2 receptors: therapeutic targets in occlusive and aneurysmal vascular diseases

PGE2 受体：闭塞性和动脉瘤性血管疾病的治疗靶点

• 批准号: 8208059
• 负责人: DOMENICK J FALCONE
• 金额: $ 41.83万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208059
• 关键词: Agonist; Aneurysm; Angiotensin II; Aorta; Apolipoprotein E; Area; Arterial Fatty Streak; Arteries; Attenuated; Binding; Blood Vessels; Bypass; Cardiovascular system; Cell Line; Cells; Clinical Trials; Coxibs; Development; Dinoprostone; Disease; EP4 receptor; Eicosanoids; Endothelial Cells; Endothelium; Environment; Enzymes; Epoprostenol; Event; Experimental Models; Exudate; Feedback; Frequencies; Gelatinase B; Generations; Goals; In Vitro; Inflammatory; Injury; Interleukin-6; Lead; Lesion; Link; Mediating; Messenger RNA; Morbidity - disease rate; Mus; Myocardial Infarction; Oral Administration; Oxidoreductase; Peptide Hydrolases; Process; Production; Prostaglandins; Recruitment Activity; Regulation; Reporting; Role; Rupture; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Stroke; Testing; Therapeutic; Thrombosis; United States; Vascular Diseases; base; cyclooxygenase 2; cytokine; human WFDC2 protein; in vivo; macrophage; mortality; novel therapeutics; prevent; public health relevance; receptor; therapeutic target

DESCRIPTION (provided by applicant): Cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) synthesis exacerbates occlusive and aneurysmal vascular disease by inducing macrophage proteinase and inflammatory cytokine expression. Despite these observations, administration of selective COX-2 inhibitors is associated with an increased frequency of adverse cardiovascular events. This paradoxical effect is not fully understood; however evidence suggests that suppression of COX-2-dependent PGI2 synthesis by endothelium renders the vascular wall more sensitive to thrombotic stimuli. Nonetheless, blocking the pathophysiologic actions of PGE2 remains an important therapeutic goal. The overall hypothesis to be tested in this application is that blocking PGE2 binding to the EP4 prostanoid receptor can inhibit vascular MMP-9 and IL-6 expression, atherosclerotic lesion development and aneurysmal dilation without altering levels of vascular PGI2. In support of this hypothesis, we report that an EP4 antagonist or EP4 knockdown is as effective as COX-2 inhibition in blocking macrophage MMP-9 expression. Moreover, EP4-dependent signaling stimulates macrophage expression of IL-6, which is linked to COX-2 and MMP-9 expression by a positive feedback loop. Also, EP4-dependent signaling stimulates secretion of PGE2 by inducing expression of microsomal PGE synthase-1 and inhibiting expression of the degradative enzyme 15-hydoxyprostaglandin dehydrogenase. Finally, inhibiting PGE2 binding to EP4 has little impact on the generation of thromboprotective PGI2 by macrophages and endothelial cells in vitro. To test the validity of our hypothesis, we propose the following specific aims: [1] Determine the role of EP4- dependent signaling on the regulation of enzymes downstream of COX-2 that regulate PGE2 synthesis and degradation by macrophages; [2] Determine the role of COX-2 and EP4-dependent signaling on the regulation of smooth muscle cell MMP-9 expression; [3] Determine whether blocking PGE2 binding to EP4 attenuates atherosclerotic lesion development in ApoE-/- mice without altering vascular prostanoid profiles; and [4] Determine whether blocking PGE2 binding to EP4 attenuates the development of angiotensin II-induced aneurysms in ApoE-/- mice without altering vascular prostanoid profiles. If successful, these studies will provide the basis for a novel therapeutic strategy to modulate occlusive and aneurysmal disease. PUBLIC HEALTH RELEVANCE: Complications of atherosclerotic and aneurysmal vascular diseases remain a major cause of morbidity and mortality in the United States. Prostaglandin E2 (PGE2), secreted by inflammatory cells recruited to the arterial wall, triggers processes that weaken the wall and lead to rupture and thrombosis. Cyclooxygenase-2 (COX-2) is an important regulator of PGE2 synthesis. It was thought that selective COX-2 inhibitors would attenuate vascular lesion development by inhibiting PGE2 synthesis. However, administration of COX-2 inhibitors surprisingly caused an increased frequency of cardiovascular complications. This unexpected effect is not fully understood; however evidence suggests that COX-2 inhibitors also block PGI2 synthesis by cells lining blood vessels, which renders the artery more sensitive to injury. Nonetheless, blocking PGE2-induced weakening of the arterial wall remains an important therapeutic goal. In proposed studies, we are attempting to bypass the unwanted effect of COX-2 inhibition on PGI2 synthesis by blocking the prostanoid receptor that mediates the pathophysiologic actions of PGE2 rather than inhibiting COX-2. If successful, these studies will provide the basis for novel therapeutic strategies to reduce the complications of atherosclerotic and aneurysmal vascular diseases.

描述(申请人提供)：环氧合酶-2(COX-2)依赖的前列腺素E2(PGE2)的合成通过诱导巨噬细胞蛋白酶和炎性细胞因子的表达而加重闭塞性和动脉瘤性血管疾病。尽管有这些观察，选择性COX-2抑制剂的应用与不良心血管事件的发生率增加有关。这种矛盾的效应还没有完全被理解；然而，证据表明，内皮抑制COX-2依赖的PGI2的合成使血管壁对血栓刺激更加敏感。尽管如此，阻断PGE2的病理生理作用仍然是一个重要的治疗目标。在这一应用中需要检验的总体假设是，阻断PGE2与EP4前列腺素受体的结合可以在不改变血管PGI2水平的情况下抑制血管MMP-9和IL-6的表达、动脉粥样硬化病变的发展和动脉瘤的扩张。为了支持这一假设，我们报告了EP4拮抗剂或EP4基因敲除与COX-2抑制一样有效地阻断巨噬细胞基质金属蛋白酶-9的表达。此外，EP4依赖的信号刺激巨噬细胞表达IL-6，而IL-6通过正反馈环路与COX-2和MMP9的表达联系在一起。此外，EP4依赖的信号通过诱导微粒体PGE合成酶-1的表达和抑制降解酶15-羟基前列腺素脱氢酶的表达来刺激PGE2的分泌。最后，抑制PGE2与EP4的结合在体外对巨噬细胞和内皮细胞产生血栓保护性PGI2的影响不大。为了验证我们假设的有效性，我们提出了以下具体目标：[1]确定EP4依赖的信号在调节巨噬细胞合成和降解PGE2的COX-2下游酶上的作用；[2)确定COX-2和EP4依赖的信号在调节平滑肌细胞MMP9表达上的作用；[3]确定阻断PGE2与EP4的结合是否在不改变血管前列腺素样蛋白的情况下减缓ApoE-/-小鼠的动脉粥样硬化病变的发展；和[4]确定阻断PGE2与EP4的结合是否在不改变血管前列腺素样蛋白的情况下减缓血管紧张素II诱导的载脂蛋白E-/-小鼠动脉瘤的发展。如果成功，这些研究将为调整闭塞性和动脉瘤性疾病的新治疗策略提供基础。 公共卫生相关性：动脉粥样硬化性和动脉瘤性血管疾病的并发症仍然是美国发病率和死亡率的主要原因。前列腺素E2(PGE2)由炎症细胞分泌到动脉壁，触发削弱动脉壁并导致破裂和血栓形成的过程。环氧合酶-2(COX-2)是前列腺素E_2合成的重要调节因子。有研究认为选择性COX-2抑制剂可能通过抑制PGE2的合成来抑制血管病变的发展。然而，令人惊讶的是，服用COX-2抑制剂会增加心血管并发症的发生率。这种意想不到的影响并不完全清楚；然而，有证据表明，COX-2抑制剂也可以通过血管内壁细胞阻止PGI2的合成，从而使动脉对损伤更加敏感。尽管如此，阻断PGE2诱导的动脉壁变弱仍然是一个重要的治疗目标。在提出的研究中，我们试图通过阻断介导PGE2病理生理作用的前列腺素受体而不是抑制COX-2来绕过COX-2抑制PGI2合成的不良影响。如果成功，这些研究将为减少动脉粥样硬化性和动脉瘤性血管疾病并发症的新治疗策略提供基础。