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

高血压终末器官损伤：PGE2 和 EP4 受体的保护作用

• 批准号: 8795212
• 负责人: PAMELA HARDING
• 金额: $ 32.66万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795212
• 关键词: Accounting; Acute; Address; Adult; Aftercare; Age Reporting; Agonist; Angiotensin II; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apoptosis; Arachidonic Acids; Binding; C57BL/6 Mouse; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Chemotaxis; Chronic; Coupled; Cyclic AMP; Dependovirus; Development; Dilatation - action; Dilated Cardiomyopathy; Dinoprostone; Disease; Doctor of Medicine; EFRAC; EP4 receptor; Enzyme-Linked Immunosorbent Assay; Event; Fibroblasts; Fibrosis; Flow Cytometry; Fractalkine; Generations; Growth Factor; Heart; Heart Hypertrophy; Heart failure; Hypertension; Hypertrophy; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Infusion procedures; Instruction; Isoproterenol; Lead; Left ventricular structure; Maintenance; Matrix Metalloproteinases; Measures; Mediating; Membrane; Migration Assay; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Myocardial Infarction; Myocardium; NADPH Oxidase; Organ; Oxidative Stress; PKA inhibitor; Pathogenesis; Population; Principal Investigator; Production; Prostaglandins; Receptor Inhibition; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Serotyping; Signal Pathway; Signal Transduction; Small Interfering RNA; Staining method; Stains; Superoxides; Techniques; Testing; Time; Transfection; United States; Western Blotting; Wild Type Mouse; analog; cardiovascular risk factor; caspase-3; cell type; chemokine; clinically relevant; cyclooxygenase 2; cytokine; human MMP14 protein; human WFDC2 protein; hypertension treatment; improved; in vivo; macrophage; male; migration; mortality; mouse model; neutralizing antibody; novel; novel therapeutics; older patient; prevent; receptor; research study; response; treatment strategy

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.

不受控制的高血压（HTN）是最终器官损伤（EOD）的主要原因，也是危险因素 心血管发病率和死亡率。虽然前列腺素E2（PGE2）在历史上被认为是 炎症的调解人，最近的证据表明它可能是抗炎或抗炎。取决于 关于特定的PGE2 EP受体亚型的参与，该亚型通过发散信号通路发出信号。 我们以前报道说，在心肌细胞上缺乏EP4受体的老年雄性小鼠发育心脏 失败的特征是射血分数减少，左心室扩张和纤维化。加上高架 左心室中趋化因子（Fractalkine和MCP-5）的表达。该提案研究了是否 PGE2通过EP4的保护性和抗炎作用是通过降低的分面和MCP-5介导的。它 检验了一个普遍的假设，即由PGE2激活的EP4降低了在血管紧张素II中发生的EOD （ANG LL）依赖性高血压和心肌梗死（ML），通过抑制产生和/或释放 炎性趋化因子分裂和MCP-5。目的我将研究PGE2是否通过其EP4受体 通过其EP4受体和心脏cAMP降低Fractalkine和MCP-5的生产和/或分泌 心肌细胞和成纤维细胞反对ANG II的有害作用。 AIM II将研究EP4是否 分子碱和/或MCP-5的依赖减少在体内和体外改善心脏功能。目标II 将研究PGE2是否通过其EP4受体以及分子烷和/或MCP-5合成的抑制和/或 释放通过在ANG LL-模型中减少炎症细胞浸润到心肌中来防止EOD 依赖的HTN和心肌梗塞（ML）。该提案将利用一种新型鼠标模型和 最先进的分子技术来解决这些目标。这些研究至关重要 确定PGE2和EP4在心脏肥大和EOD中的作用。第二个项目与：1）密切相关 I和III的项目也研究了EOD的发病机理； 2）IV项目还研究了T I受体 和超氧化物； 3）III项目，还研究了花生四烯酸代谢产物。项目第二将使用全部4 内核。 相关性（请参阅说明）： 如果实现了拟议的目标，我们将了解PGE2和EP4在维护中的作用 心脏功能。 PGE2通过EP4的保护性和抗炎作用具有重要意义 在各种条件下服用NSAID的人数。我们的研究可能导致新的发展 治疗高血压，心肌梗塞和最终器官损伤的治疗策略。