Role of 20-HETE in Endothelial Dysfunction

20-HETE 在内皮功能障碍中的作用

• 批准号: 7137827
• 负责人: Michal Laniado Schwartzman
• 金额: $ 32.73万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7137827
• 关键词: blood pressure; cytochrome P450; eicosanoid metabolism; gene expression; hormone regulation /control mechanism; hypertension; laboratory rat; vascular endothelium; vasomotion

This is a proposal to investigate the function and regulation of 20-hydroxyeicosatetraenoic acid (20- HETE) synthesis in the vasculature, more specifically, its participation in endothelium dysfunction in models of increased vascular expression of cytochrome P450 (CYP) 4A. 20-HETE is a primary eicosanoid in the microcirculation where it participates in the regulation of vascular tone. In rat renal arteries, CYP4A expression and 20-HETE production increased with decreased arterial diameter. CYP4A overexpression in small arteries and arterioles increased vascular reactivity and myogenic tone. Recent studies and preliminary results suggest that the endothelium is a target for 20-HETE bioactions. Smooth muscle-specific CYP4A1 expression via Ad-SM22-4A1 induces a marked CYP4A-dependent and 20-HETE-mediated endothelial sprouting in renal arterial microvessels. In vitro, 20-HETE is a potent angiogenic factor stimulating capillary-like tube formation of endothelial cells by a mechanism that may include MAPK activation and induction of inflammatory and angiogenic proteins (IL-8 and VEGF). In vivo, intravenous injection of Adv-CYP4A2 causes hypertension and renal arteries from these rats display endothelial dysfunction, which can be reversed by inhibition of CYP4A activity. Arteries from Adv-CYP4A2-transduced rats produce more 20-HETE and less NO; they also express higher levels of inflammatory proteins (ICAM and VCAM). These findings raise the possibility that vascular 20-HETE is an important determinant of endothelial dysfunction, a condition that is characterized by decreased NO bioavailability and enhanced endothelial activation, and are the basis for the proposal's hypothesis: Vascular overexpression of CYP4A fosters prohypertensive mechanisms via increased production of 20-HETE in a manner that may include endothelial dysfunction and activation. This hypothesis will be tested by 1) determining the relationship between hypertension, endothelial dysfunction and activation, CYP4A expression and 20-HETE synthesis; 2) determining whether the functional consequences of increased vascular expression of CYP4A is associated with endothelial expression and synthesis of CYP4A and 20-HETE, respectively; and 3) exploring mechanisms underlying 20-HETE mediated endothelial dysfunction and activation.

本提案旨在研究 20-羟基二十碳四烯酸（20- HETE）在脉管系统中的合成，更具体地说，它参与内皮功能障碍 细胞色素 P450 (CYP) 4A 血管表达增加的模型。 20-HETE 是主要的 类二十烷酸在微循环中参与血管张力的调节。在大鼠肾 随着动脉直径的减小，CYP4A 的表达和 20-HETE 的产生增加。 小动脉和小动脉中 CYP4A 的过度表达增加了血管反应性和肌源性张力。 最近的研究和初步结果表明内皮细胞是 20-HETE 生物作用的目标。 通过 Ad-SM22-4A1 平滑肌特异性 CYP4A1 表达诱导显着的 CYP4A 依赖性 和 20-HETE 介导的肾动脉微血管内皮出芽。在体外，20-HETE 是 强效血管生成因子通过机制刺激内皮细胞毛细血管样管形成 可能包括 MAPK 激活以及炎症和血管生成蛋白（IL-8 和 血管内皮生长因子）。在体内，静脉注射 Adv-CYP4A2 会导致高血压和肾动脉 这些大鼠表现出内皮功能障碍，可以通过抑制 CYP4A 活性来逆转。 Adv-CYP4A2 转导大鼠的动脉产生更多的 20-HETE 和更少的 NO；他们还表示 炎症蛋白（ICAM 和 VCAM）水平较高。这些发现提出了这样的可能性： 血管20-HETE是内皮功能障碍的重要决定因素，内皮功能障碍是 其特点是 NO 生物利用度降低和内皮活性增强，是基础 该提案的假设：CYP4A 的血管过度表达可促进高血压 通过增加 20-HETE 的产生来实现机制，其方式可能包括内皮细胞 功能障碍和激活。该假设将通过以下方式进行检验：1）确定之间的关系 高血压、内皮功能障碍和激活、CYP4A 表达和 20-HETE 合成； 2） 确定 CYP4A 血管表达增加的功能后果是否 分别与 CYP4A 和 20-HETE 的内皮表达和合成相关；和 3) 探索 20-HETE 介导的内皮功能障碍和激活的机制。