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

失控高血压(HTN)是终末器官损害(EOD)的主要原因，也是 心血管发病率和死亡率。尽管前列腺素E2(PGE2)历史上被认为是一种 炎症介质，最近的证据表明它可能是促炎或抗炎的；取决于 关于特定的PGE2 EP受体亚型的参与，这些亚型通过不同的信号通路发出信号。 我们之前曾报道，心肌细胞上缺乏EP4受体的老年雄性小鼠会发生心脏 心力衰竭的特征是射血分数降低、左心室扩大和纤维化； 趋化因子(Fractalkine和MCP-5)在左心室的表达。这项提案考察了 PGE2通过EP4的保护和抗炎作用是通过减少的Fractalkine和MCP-5介导的。它 测试由PGE2激活的EP4可减少血管紧张素II中的EOD这一普遍假设 (AngⅡ)依赖性高血压和心肌梗死(Ml)通过抑制产生和/或释放 炎性趋化因子Fractalkine和MCP-5。目的研究前列腺素E_2是否通过其EP4受体 通过其EP4受体和cAMP减少心脏组织中Fractalkine和MCP-5的产生和/或分泌 抗血管紧张素转换酶II的有害作用。 依赖于Fractalkine和/或MCP-5的减少可以改善体内和体外的心功能。AIM II 将研究PGE2是否通过其EP4受体和抑制Fractalkine和/或MCP-5的合成和/或 释放通过减少炎症细胞对心肌的侵袭来预防EOD 依赖性HTN和心肌梗死(Ml)。该提案将利用一种新的鼠标模型，与 最先进的分子技术来解决这些目标。这些研究在以下方面具有至关重要的意义 测定PGE2和EP4在心肌肥厚和EOD中的作用。项目二与以下内容密切相关：1) 项目I和项目III，它也研究EOD的发病机制；2)项目IV，它也研究ATI受体 和超氧化物；以及3)项目III，该项目也研究花生四烯酸代谢物。项目II将使用所有4个 核心。 相关性(请参阅说明)： 如果建议的目标得以实现，我们将了解PGE2和EP4在维持 心脏功能。前列腺素E_2通过EP4发挥保护和抗炎作用具有重要意义 因各种情况服用非甾体抗炎药的人数。我们的研究可能会导致新的 治疗高血压、心肌梗死和终末器官损害的治疗策略。

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.