CYP2J2 Derived Eicosanoids and Endothelial Function

CYP2J2 衍生的类二十烷酸和内皮功能

• 批准号: 6806488
• 负责人: CRAIG R LEE
• 金额: $ 5.31万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6806488
• 关键词: arachidonate; atherosclerosis; biological models; blood pressure; cardiovascular disorder; clinical research; cytochrome P450; eicosanoids; genetically modified animals; human genetic material tag; human morbidity; human mortality; human tissue; immunocytochemistry; inflammation; laboratory mouse; nitric oxide; northern blottings; postdoctoral investigator; single nucleotide polymorphism; southern blotting; western blottings

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.

描述（由申请方提供）：人细胞色素P450 2 J2（CYP 2 J2）在内皮细胞中将花生四烯酸（AA）氧化代谢为环氧二十碳三烯酸（E3）。在冠状动脉微循环和外周血管系统中，内皮素具有强有力的血管扩张和抗炎作用，并可能作为一氧化氮的重要储备系统。然而，该途径的生理功能尚未在整个动物模型或人类中得到很好的表征。由于在心血管疾病患者中观察到一氧化氮系统受损，并且“内皮功能障碍”对疾病发病机制有显著贡献，因此内皮CYP 2 J2活性可能具有临床重要性。CYP 2 J2基因的单核苷酸多态性在心血管疾病的发生、发展中起着重要作用。为了表征CYP 2 J2在血管系统中的生理功能，并评价该代谢途径在心血管疾病患者中的潜在临床重要性，本提案旨在：（1）使用鼠Tie 2启动子开发具有人CYP 2 J2的内皮特异性过表达的转基因小鼠模型，（2）表征组成性增加的CYP 2 J2的体内作用，CYP 2 J2介导的内皮EET生物合成对这些小鼠血压和血管内炎症的调节，和（3）确定编码CYP 2 J2的基因中的多态性是否影响人类动脉粥样硬化疾病的发展和/或进展。