Functional implications of a newly characterized pathway of 11,12-epoxyeicosatrienoic acid metabolism in arterial smooth muscle
Functional implications of a newly characterized pathway of 11,12-epoxyeicosatrienoic acid metabolism in arterial smooth muscle
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DOI：
10.1161/01.res.79.4.784
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发表时间：
1996-10-01
影响因子：
20.1
通讯作者：
Spector, AA
中科院分区：
文献类型：
--
作者：
Fang, X;Kaduce, TL;Spector, AA
环氧二碳三烯酸（EETs）是一种有效的血管扩张剂，来源于花生四烯酸的细胞色素P-450代谢。eet快速转化为相应的二羟基二碳三烯酸（DHETs）被认为是eet具有生物活性的过程。然而，EET的血管代谢和EET代谢物的血管活性尚未得到广泛研究。因此，在猪主动脉平滑肌细胞中表征了11,12- eet的代谢。细胞将[H-3]11,12- eet转化为11,12- dhet和新鉴定的代谢物7,8-二羟基十六烯酸（DHHD）。11,12- dhet在培养基中的积累量在2 ~ 4 h达到最大值，然后下降，而7,8- dhhd的积累量持续增加，超过11,12- dhet的量8 h。[H-3]11,12- eet在未标记的11,12- dhet存在下转化为放射性标记的7,8- dhhd减少，表明11,12- dhet是11- i2 - eet转化为7,8- dhhd的中间体。这与11,12- eet通过环氧化物水解酶转化为11,12- dhet的途径是一致的。然后经过两次氧化形成7,8- dhhd。在猪冠状动脉环中，11,12- dhet与11,12- eet在5 mu mol/L时产生的松弛程度相似（分别为77%和64%）。7,8- dhhd也产生血管松弛。因此，11,12- eet的血管活性不会因转化为11,12- dhet和7,8- dhhd而消除。这些结果表明11,12- dhet及其代谢物7,8- dhhd可能参与调节猪冠状动脉和其他血管组织的血管张力。
Epoxyeicosatrienoic acids (EETs) are potent vasodilators derived from cytochrome P-450 metabolism of arachidonic acid. The rapid conversion of EETs to their corresponding dihydroxyeicosatrienoic acids (DHETs) has been proposed as a process whereby EETs are rendered biologically inactive. However, the vascular metabolism of EETs and the vasoactivities of EET metabolites have not been extensively studied. Accordingly, 11,12-EET metabolism was characterized in porcine aortic smooth muscle cells. The cells converted [H-3]11,12-EET to 11,12-DHET and to a newly identified metabolite, 7,8-dihydroxy-hexadecadienoic acid (DHHD). 11,12-DHET accumulation in the medium reached a maximum in 2 to 4 hours and then declined, whereas 7,8-DHHD accumulation increased continuously and exceeded the amount of 11,12-DHET by 8 hours. [H-3]11,12-EET conversion to radiolabeled 7,8-DHHD was reduced in the presence of unlabeled 11,12-DHET, indicating that 11,12-DHET is an intermediate in the conversion of 11-I2-EET to 7,8-DHHD. This is consistent with a pathway whereby 11,12-EET is converted by an epoxide hydrolase to 11,12-DHET. which then undergoes two beta-oxidations to form 7,8-DHHD. In porcine coronary artery rings contracted with a thromboxane mimetic, 11,12-DHET produced relaxation similar in magnitude to that produced by 11,12-EET (77% versus 64% relaxation at 5 mu mol/L, respectively). 7,8-DHHD also produced vasorelaxation. Thus, the vasoactivity of 11,12-EET is not eliminated by conversion to 11,12-DHET and 7,8-DHHD. These results suggest that 11,12-DHET and its metabolite, 7,8-DHHD, may contribute to the regulation of vascular tone in the porcine coronary artery and possibly other vascular tissues.