Hypertensive End Organ Damage: Protective Role of PGE2 and EP4 Receptor

不受控制的高血压（HTN）是终末器官损害（EOD）的主要原因，也是高血压的危险因素。 心血管疾病发病率和死亡率。虽然前列腺素E2（PGE 2）在历史上被认为是一种 作为炎症介质，最近的证据表明它可能是促炎或抗炎的;这取决于 参与特定的PGE 2 EP受体亚型，通过不同的信号传导途径发出信号。 我们以前报道过，老年雄性小鼠缺乏心肌细胞上的EP 4受体， 以射血分数降低、左心室扩张和纤维化为特征的衰竭;加上升高的 趋化因子（fractalkine和MCP-5）在左心室中的表达。这项建议审查了 PGE 2通过EP 4的保护和抗炎作用由减少的Fractalkine和MCP-5介导。它 测试了一般假设，即由PGE 2激活的EP 4减少了血管紧张素II中发生的EOD。 (Ang II）-依赖性高血压和心肌梗塞（MI），通过抑制 炎性趋化因子fractalkine和MCP-5。目的研究前列腺素E2（PGE 2）是否通过其EP 4受体 通过其EP 4受体和cAMP减少心脏中Fractalkine和MCP-5的产生和/或分泌 肌细胞和成纤维细胞，并对抗Ang II的有害作用。Aim II将研究EP 4是否 Fractalkine和/或MCP-5的依赖性降低在体内和体外均改善心脏功能。Aim II 将研究PGE 2是否通过其EP 4受体和抑制fractalkine和/或MCP-5合成和/或 释放通过减少炎性细胞向心肌中的浸润来防止EOD。 依赖性HTN和心肌梗死（MI）。该提案将利用一种新的小鼠模型， 最先进的分子技术来实现这些目标。这些研究对 确定PGE 2和EP 4在心脏肥大和EOD中的作用。项目II与以下方面密切相关：1） 项目I和III也研究EOD的发病机理; 2）项目IV也研究A T I受体 和超氧化物;和3）项目III，也研究花生四烯酸代谢物。项目II将使用所有4个 丹 相关性（参见说明）： 如果实现了所提出的目标，我们将了解PGE 2和EP 4在维持 心脏功能PGE 2通过EP 4的保护和抗炎作用具有重要意义， 服用NSAIDS治疗各种疾病的人数。我们的研究可能会导致新的 用于治疗高血压、心肌梗死和终末器官损伤的治疗策略。

Uncontrolled hypertension (HTN) is a major cause of end organ damage (EOD) and a risk factor for cardiovascular morbidity and mortality. Although prostaglandin E2 (PGE2) was historically thought to be a mediator of inflammation, more recent evidence suggests that it may be pro or anti-inflammatory; depending on the involvement of specific PGE2 EP receptor sub-types that signal through divergent signaling pathways. We previously reported that aged male mice lacking the EP4 receptor on cardiomyocytes develop heart failure characterized by reduced ejection fraction, left ventricle dilatation and fibrosis; coupled with elevated expression of chemokines (fractalkine and MCP-5) in the left ventricle. This proposal examines whether the protective and anti-inflammatory effects of PGE2 via EP4 are mediated by reduced fractalkine and MCP-5. It tests the general hypothesis that EP4, activated by PGE2, reduces the EOD that occurs in Angiotensin II (Ang ll)-dependent hypertension and myocardial infarction (Ml) by inhibiting the production and/or release of the inflammatory chemokines fractalkine and MCP-5. Aim I will study whether PGE2 via its EP4 receptor reduces production and/or secretion of fractalkine and MCP-5 via its EP4 receptor and cAMP in cardiac myocytes and fibroblasts and opposes the deleterious effects of Ang II. Aim II will study whether EP4 dependent reductions in fractalkine and/or MCP-5 improve cardiac function both in vivo and in vitro. Aim II will study whether PGE2 via its EP4 receptor and inhibition of fractalkine and/or MCP-5 synthesis and/or release prevents EOD by reducing infiltration of inflammatory cells into the myocardium in models of Ang ll- dependent HTN and myocardial infarction (Ml). The proposal will utilize a novel mouse model coupled with state-of-the art molecular techniques to address these aims. These studies are of utmost importance in determining the role of PGE2 and EP4 in cardiac hypertrophy and EOD. Project II is closely related to: 1) Projects I and III which also study the pathogenesis of EOD; 2) Project IV which also studies A T I receptors and superoxide; and 3) Project III which also studies arachidonic acid metabolites. Project II will use all 4 Cores. RELEVANCE (See instructions): If the proposed aims are achieved, we will understand the role of PGE2 and EP4 in the maintenance of cardiac function. The protective and anti-inflammatory effect of PGE2 via EP4 is of great significance given the number of people taking NSAIDS for a variety of conditions. Our study could lead to development of new therapeutic strategies for the treatment of hypertension, myocardial infarction, and end organ damage.