THE ROLE OF GENETIC POLYMORPHISMS IN THE EPOXYGENASE PATHWAY IN HYPERTENSION

基因多态性在高血压环氧合酶途径中的作用

• 批准号: 7376262
• 负责人: ALBERT W DREISBACH
• 金额: $ 2.35万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376262
• 关键词: ROLE; GENETIC; POLYMORPHISMS; EPOXYGENASE; PATHWAY

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Essential hypertension is a major risk factor for cardiovascular disease which is the leading cause of death in the United States. Over 50 million Americans are effected by essential hypertension but its mechanisms have yet to be defined. Vasoactive arachidonic acid metabolites of the cytochrome P450 (CYP) epoxygenase pathway, the epoxides, have been implicated in animal and human studies of hypertension. Hypertension is a common problem in patients with varying degrees of chronic renal failure. The epoxide 11, 12-epieicosatrienoic acid (11, 12-EET), the putative endothelium derived hyperpolarizing factor (EDHF) is formed by CYP2C9, CYP2C8, and converted to the corresponding DHET by the soluble epoxide hydrolase (sEH). CYP2C9, CYP2C8 and sEH exhibit a high prevalence of genetic polymorphisms which may lead to altered levels of epoxides and reduced formation of EDHF in hypertensive patients. The perturbed vasoactive epoxide profile produced by genetic polymorphisms in this pathway may play a major mechanistic role in a subgroup of patients with hypertension. If we detect a greater frequency of these mutant alleles in a hypertensive population then a genetic test could be developed to identify subgroups of patients at risk for the development of hypertension allowing early intervention. These results accompanied with altered levels of epoxides and brachial artery reactivity would also suggest that the epoxygenase pathway may be a novel therapeutic target for the development of drugs to treat hypertension. Investigations of altered brachial artery reactivity and eiconsanoid levels in normotensive subjects may demonstrate preclinical endothelial dysfunction produced by mutant epoxygenase genotypes. Further studies could be performed in patients with varying degrees of chronic renal failure to investigate whether this pathway is involved with hypertension associated with CRF.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。原发性高血压是心血管疾病的主要危险因素，而心血管疾病是美国的主要死亡原因。超过 5000 万美国人患有原发性高血压，但其机制尚未明确。细胞色素 P450 (CYP) 环氧化酶途径的血管活性花生四烯酸代谢物（环氧化物）与动物和人类高血压研究有关。高血压是不同程度慢性肾功能衰竭患者的常见问题。环氧化物 11, 12-表二十碳三烯酸 (11, 12-EET)，即假定的内皮源性超极化因子 (EDHF)，由 CYP2C9、CYP2C8 形成，并通过可溶性环氧化物水解酶 (sEH) 转化为相应的 DHET。 CYP2C9、CYP2C8 和 sEH 表现出高患病率的遗传多态性，可能导致高血压患者环氧化物水平改变并减少 EDHF 形成。该途径中的基因多态性产生的血管活性环氧化物谱的扰动可能在高血压患者亚组中发挥主要的机制作用。 如果我们在高血压人群中检测到这些突变等位基因的频率更高，那么就可以开发基因测试来识别有高血压风险的患者亚组，从而进行早期干预。这些结果伴随着环氧化物和肱动脉反应性水平的改变，也表明环氧化酶途径可能是开发治疗高血压的药物的新治疗靶点。对血压正常受试者的肱动脉反应性和类花生酸水平改变的研究可能证明突变型环氧化酶基因型导致临床前内皮功能障碍。可以在不同程度的慢性肾功能衰竭患者中进行进一步的研究，以调查该通路是否与 CRF 相关的高血压有关。