THE ROLE OF GENETIC POLYMORPHISMS IN THE EPOXYGENASE PATHWAY IN HYPERTENSION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，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死亡的主要原因。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，已在高血压的动物和人类研究中涉及。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 -表二碳三烯酸（11,12 - eet），被认为是内皮衍生的超极化因子（EDHF），由CYP2C9、CYP2C8形成，并通过可溶性环氧化物水解酶（sEH）转化为相应的二氢内酯。CYP2C9、CYP2C8和sEH表现出较高的遗传多态性，这可能导致高血压患者环氧化物水平改变和EDHF形成减少。在这一途径中由遗传多态性产生的血管活性环氧化物谱紊乱可能在高血压患者亚组中起主要的机制作用。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，那么就可以开发出一种基因检测方法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水平和肱动脉反应性的改变，也表明环氧化酶途径可能是开发治疗高血压药物的新靶点。对血压正常者肱动脉反应性和类血管内皮素水平改变的研究可能证明由突变的环氧合酶基因型引起的临床前内皮功能障碍。进一步的研究可以在不同程度的慢性肾功能衰竭患者中进行，以调查该途径是否与慢性肾功能衰竭相关的高血压有关。

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.