Role of 20-HETE in Endothelial Dysfunction

本文建议研究20-羟基二十碳四烯酸(20-羟基二十碳四烯酸)的功能和调节。 HETE)在血管系统中的合成，更具体地说，它参与了血管内皮功能障碍 血管细胞色素P450(CYP)4A表达增加的模型。20-HETE是主要的 在微循环中，它参与调节血管张力的二十烷类化合物。在大鼠肾脏中 随着动脉管径的减小，动脉壁细胞色素P4A的表达和20-羟色胺的生成增加。 细胞色素P4A在小动脉和小动脉的过度表达增加了血管的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生物作用的靶点。 通过Ad-SM22-4A1表达的平滑肌特异性细胞色素P4A1诱导显著的细胞色素P4A依赖 20-HETE介导的肾动脉微血管内皮细胞发芽。在体外，20-HETE是一种 强效血管生成因子刺激内皮细胞毛细血管样管形成的机制 这可能包括MAPK的激活和诱导炎性和血管生成蛋白(IL-8和 血管内皮细胞生长因子)。在体内，静脉注射ADV-CYP4A2会引起高血压和肾动脉病变。 这些大鼠表现出内皮功能障碍，这种功能障碍可以通过抑制细胞色素P4A活性来逆转。 转导ADV-CYP4A2的大鼠动脉产生更多的20-HETE和更少的NO；它们还表达 炎性蛋白(ICAM和VCAM)水平较高。这些发现增加了这样一种可能性 血管20-HETE是内皮功能障碍的重要决定因素，这种情况 以NO生物利用度降低和内皮激活增强为特征，是 支持该提议的假说：血管中过度表达细胞色素P4A可促进高血压 通过增加20-HETE的产生而产生的机制可能包括内皮 功能障碍和激活。这一假设将通过1)确定以下关系来检验 高血压、内皮功能障碍和活化、CYP4A表达和20-HETE合成；2) 确定血管中细胞色素P4A表达增加的功能后果是否 分别与内皮细胞表达和合成CYP4A和20-HETE相关；3) 探索20-HETE介导的内皮功能障碍和激活的机制。

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.