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.

这是研究20-羟基乙烯酸的功能和调节的建议（20- 脉管系统中的合成，更具体地说，其参与内皮功能障碍 细胞色素P450（CYP）4A血管表达增加的模型。 20-Hete是主要的 微循环中的类花生酸参与血管张力的调节。在大鼠肾脏中 动脉，CYP4A表达和20-HETE产生随动脉直径降低而增加。 小动脉和小动脉中的CYP4A过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，内皮是20-HETE生物措施的靶标。 通过AD-SM22-4A1表达平滑肌特异性的CYP4A1 以及肾动脉微血管中的20-Hete介导的内皮发芽。在体外，20-Hete是一个 有效的血管生成因子通过一种机制刺激内皮细胞形成毛细管样管 这可能包括MAPK激活以及炎症和血管生成蛋白的诱导（IL-8和 VEGF）。在体内，静脉注射ADV-CYP4A2会引起高血压和肾动脉 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。 来自ADV-CYP4A2转导的大鼠的动脉产生更多的20-HETE，更少的NO；他们也表达 较高水平的炎性蛋白（ICAM和VCAM）。这些发现增加了 血管20-HETE是内皮功能障碍的重要决定因素，这种情况是 其特征是没有生物利用度降低和增强的内皮激活，并且是基础 对于该提议的假设：CYP4A的血管过表达促进了型的 通过可能包括内皮的方式增加20-HETE的产生的机制 功能障碍和激活。该假设将通过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CYP4A血管表达增加的功能后果是否是 分别与CYP4A和20-HETE的内皮表达和合成有关； 3） 探索20-HETE介导的内皮功能障碍和激活的机制。