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: 8460616
• 负责人: PAMELA HARDING
• 金额: $ 33.12万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8460616
• 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）是终末器官损伤（EOD）的主要原因，也是导致高血压的危险因素。 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 炎症介质，最近的证据表明它可能具有促炎或抗炎作用；取决于 涉及通过不同信号传导途径发出信号的特定 PGE2 EP 受体亚型。 我们之前报道过，心肌细胞上缺乏 EP4 受体的老年雄性小鼠发育出心脏 以射血分数降低、左心室扩张和纤维化为特征的衰竭；再加上升高的 左心室趋化因子（fractalkine 和 MCP-5）的表达。该提案审查是否 PGE2 通过 EP4 的保护和抗炎作用是由还原的 fractalkine 和 MCP-5 介导的。它 检验一般假设，即由 PGE2 激活的 EP4 会减少血管紧张素 II 中发生的 EOD 通过抑制 (Ang II) 的产生和/或释放来治疗 (Ang II) 依赖性高血压和心肌梗死 (MI) 炎症趋化因子 fractalkine 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 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EP4是否 fractalkine 和/或 MCP-5 的依赖性减少可改善体内和体外心脏功能。目标二 将研究 PGE2 是否通过其 EP4 受体并抑制 fractalkine 和/或 MCP-5 合成和/或 在Ang ll-模型中，释放通过减少炎症细胞向心肌的浸润来预防EOD 依赖HTN和心肌梗塞(MI)。该提案将利用一种新颖的小鼠模型以及 最先进的分子技术来实现这些目标。这些研究对于 确定 PGE2 和 EP4 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 的发病机制； 2) 项目 IV 也研究 A T I 受体 和超氧化物； 3）项目III也研究花生四烯酸代谢物。项目 II 将使用全部 4 个 核心。 相关性（参见说明）： 如果所提出的目标得以实现，我们将了解 PGE2 和 EP4 在维持 心脏功能。 PGE2 通过 EP4 发挥的保护和抗炎作用具有重要意义 因各种病症服用非甾体抗炎药的人数。我们的研究可能会导致新的开发 治疗高血压、心肌梗塞和终末器官损伤的治疗策略。