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.

本研究旨在探讨20-羟基二十碳四烯酸（20-hydroxyyeicosatetraenoic acid，20-HA）在细胞内的功能和调控。 HETE）合成，更具体地说，它参与血管内皮功能障碍， 细胞色素P450（CYP450）4A血管表达增加的模型。20-HETE是主要的 类花生酸在微循环中参与血管张力的调节。大鼠肾 随着动脉直径的减小，CYP4A表达和20-HETE产生增加。 小动脉和小动脉中CYP4A过表达增加血管反应性和肌原性张力。 最近的研究和初步结果表明，内皮细胞是20-HETE生物作用的靶点。 通过Ad-SM 22 - 4A1的平滑肌特异性CYP4A1表达诱导显著的CYP4A依赖性 和20-HETE介导的肾动脉微血管内皮发芽。在体外，20-HETE是一种 通过一种机制刺激内皮细胞的毛细血管样管形成的有效的血管生成因子 这可能包括MAPK激活和诱导炎症和血管生成蛋白（IL-8和 VEGF）。在体内，静脉注射Adv-CYP4A2可导致高血压和肾动脉阻塞。 这些大鼠表现出内皮功能障碍，其可以通过抑制CYP4A活性来逆转。 来自Adv-CYP4A2转导大鼠的动脉产生更多的20-HETE和更少的NO;它们还表达 炎症蛋白（ICAM和VCAM）水平升高。这些发现提出了一种可能性， 血管20-HETE是内皮功能障碍的重要决定因素，内皮功能障碍是一种 其特征在于降低NO生物利用度和增强内皮活化，并且是基础。 该提案的假设：血管中CYP4A的过度表达促进高血压 通过增加20-HETE产生的机制，可能包括内皮细胞 功能障碍和激活。这一假设将通过以下方式进行检验：1）确定 高血压、内皮功能障碍和激活、CYP4A表达和20-HETE合成; 2） 确定CYP 4A血管表达增加的功能后果是否 分别与内皮细胞表达和CYP4A和20-HETE合成相关;和3） 探索20-HETE介导的内皮功能障碍和活化的潜在机制。