CYP2J2 Derived Eicosanoids and Endothelial Function

描述(申请人提供)：人细胞色素P450 2J2(CYP2J2)氧化代谢内皮细胞中的花生四烯酸(AA)为环氧二十碳三烯酸(EETs)。EETs在冠脉微循环和外周血管系统中具有强大的血管扩张和抗炎作用，可能是一氧化氮的重要储备系统。然而，这一途径的生理功能在整个动物模型或人类中还没有得到很好的表征。由于心血管疾病患者体内存在一氧化氮系统的损伤，“内皮功能障碍”在疾病的发病机制中起着重要作用，因此，内皮细胞的CYP2J2活性可能具有重要的临床意义。最近发现了编码CYP2J2基因的单核苷酸多态性，它可能在心血管疾病的发生和发展中起着不可或缺的作用。为了研究CYP2J2在血管系统中的生理功能，并评估这一代谢途径在心血管疾病患者中的潜在临床意义，本建议旨在：(1)利用小鼠Tie2启动子建立内皮特异性高表达人CYP2J2的转基因小鼠模型；(2)研究结构性增加的、由CYP2J2介导的内皮EET生物合成在这些小鼠的血压调节和血管内炎症中的体内作用；以及(3)确定编码CYP2J2的基因的多态性是否影响人类动脉粥样硬化性疾病的发生和/或进展。

DESCRIPTION (provided by applicant): Human cytochrome P450 2J2 (CYP2J2) oxidatively metabolizes arachidonic acid (AA) in endothelial cells to epoxyeicosatrienoic acids (EETs). The EETs possess potent vasodilatory and anti-inflammatory effects in the coronary microcirculation and peripheral vasculature, and may serve as an important reserve system to nitric oxide. However, the physiological functions of this pathway have not been well characterized in whole animal models or humans. Since impairment in the nitric oxide system is observed in patients with cardiovascular disease and "endothelial dysfunction" contributes significantly to disease pathogenesis, endothelial CYP2J2 activity may be clinically important. Single nucleotide polymorphisms in the gene encoding CYP2J2 have been identified recently, and may play an integral role in the development and progression of cardiovascular disease. In order to characterize the physiological functions of CYP2J2 in the vasculature, and evaluate the potential clinical importance of this metabolic pathway in patients with cardiovascular disease, this proposal aims to: (1) develop a transgenic mouse model with endothelial-specific overexpression of human CYP2J2 using the murine Tie2 promoter, (2) characterize the in vivo effects of constitutively increased, CYP2J2-mediated endothelial EET biosynthesis on the regulation of blood pressure and intravascular inflammation in these mice, and (3) determine if polymorphisms in the gene encoding CYP2J2 influence the development and/or progression of atherosclerotic disease in humans.