THE ROLE OF GENETIC POLYMORPHISMS IN THE EPOXYGENASE PATHWAY IN HYPERTENSION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。高血压是心血管疾病的主要危险因素，在美国，心血管疾病是导致死亡的主要原因。超过5000万美国人受到原发性高血压的影响，但其机制尚未确定。细胞色素P450(CYP)环氧合酶途径的血管活性花生四烯酸代谢产物，即环氧化物，已被用于动物和人类的高血压研究。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)是一种可能的内皮细胞源性超极化因子(EDHF)，由细胞色素P450_2C9和细胞色素P_2C_8形成，并在可溶性环氧化物水解酶(SEH)作用下转化为相应的DHET。CYP2C9、CYP2C8和sEH具有较高的遗传多态性，可能导致高血压患者体内环氧化物水平的改变和EDHF的形成。这一途径中的遗传多态所产生的血管活性环氧化物的扰动特征可能在高血压患者的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，那么就可以开发一种基因测试来识别有患高血压风险的患者亚群，从而进行早期干预。这些结果伴随着环氧化物水平和臂动脉反应性的改变，也表明环氧合酶途径可能成为治疗高血压药物开发的一个新的治疗靶点。对血压正常的受试者的臂动脉反应性和类依康康定水平改变的研究可能表明，由突变的环氧合酶基因引起的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，以调查这一途径是否与CRF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.