Altered soluble epoxide hydrolase gene expression and function and vascular disease risk in the stroke-prone spontaneously hypertensive rat
Altered soluble epoxide hydrolase gene expression and function and vascular disease risk in the stroke-prone spontaneously hypertensive rat
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DOI：
10.1161/hypertensionaha.107.102160
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发表时间：
2008-02-01
期刊：
影响因子：
8.3
通讯作者：
Fornage, Myriam
中科院分区：
文献类型：
--
作者：
Corenblum, Mandi J.;Wise, Vance E.;Fornage, Myriam
可溶性环氧化物水解酶(SEH)代谢环二十碳三烯酸，是心血管疾病治疗的新靶点。在易感性不同的自发性高血压大鼠(SHR)中，我们研究了sEH基因(EPHX2)序列变异、sEH功能和终末器官损伤风险之间的关系。卒中倾向组(SHR/A3)脑内EPHX2的表达显著低于卒中抵抗组(SHR/N)(5倍；P<；0.0001)。对这两个菌株的EPHX2启动子进行了重新测序，发现了3个显著影响启动子体外转录活性的多态。脑组织sEH酶活性和血浆花生四烯酸和亚油酸代谢物水平的测定进一步表明，两株sEH之间存在显著差异。环氧十八烯酸与二羟基十八烯酸的比值显著升高，表明SHR/A3的sEH活性低于SHR/N(P<；0.0001)。SHR/A3株血浆二羟基二十碳三烯酸水平低于SHR/N株(P<；0.0001)，而两株株血浆环氧二十碳三烯酸水平相似。对SHR/A3×SHR/N杂交F2代的EPHX2基因多态性的关联分析表明，携带EPHX2的SHR/A3等位基因的动物比不携带EPHX2等位基因的动物患中风和相关尿蛋白尿的风险更大。对多个卒中易患和卒中抵抗的SHR亚株之间的等位基因异同模式的研究表明，EPHX2属于所有易卒中但不耐卒中的亚株共有的单倍型区块。这些数据支持EPHX2基因多态性在卒中易感自发性高血压患者中对sEH基因表达、功能和终末器官损伤风险的作用。
Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids and represents a novel therapeutic target in cardiovascular disease treatment. We investigated the relationship among sequence variation in the sEH gene (Ephx2), sEH function, and risk of end-organ injury in strains of spontaneously hypertensive rat (SHRs) differing in their susceptibility to develop brain vascular disease. Brain Ephx2 expression was significantly lower in stroke-prone (SHR/A3) than in stroke-resistant (SHR/N) SHRs (5-fold; P < 0.0001). Resequencing of the Ephx2 promoter in the 2 strains identified 3 polymorphisms that significantly influenced promoter transcriptional activity in vitro. Measurements of brain sEH enzyme activity and plasma levels of arachidonate and linoleate metabolites of sEH further suggested significant differences between the 2 strains. Ratios of epoxyoctadecenoic acids to dihydroxyoctadecenoic acids were significantly higher, indicating a lower sEH activity in SHR/A3 than in SHR/N (P < 0.0001). Plasma dihydroxyeicosatrienoic acid levels were lower in SHR/A3 than in SHR/N (P < 0.0001), but plasma epoxyeicosatrienoic acids levels were similar in the 2 strains. Association analysis of Ephx2 polymorphism in the F2 progeny of an SHR/A3 x SHR/N cross showed that animals carrying the SHR/A3 allele of Ephx2 had a greater risk of stroke and associated urinary proteinuria than animals that do not. Investigation of patterns of allelic similarities and differences among multiple stroke-prone and stroke-resistant SHR substrains showed that Ephx2 belongs to a haplotype block shared among all of the stroke-prone but no stroke-resistant substrains. These data support a role for Ephx2 polymorphism on sEH gene expression and function and risk of end-organ injury in the stroke-prone SHR.