Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide
Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide
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DOI：
10.1152/ajpheart.00448.2002
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发表时间：
2002-12-01
影响因子：
4.8
通讯作者：
Spector, AA
中科院分区：
文献类型：
--
作者：
Fang, X;Weintraub, NL;Spector, AA
细胞色素P-450环氧合酶衍生的环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，ESTs）在调节血管反应性和功能中起重要作用。通过可溶性环氧化物水解酶转化为相应的二羟基二十碳三烯酸（DHEA）被认为是哺乳动物血管细胞中EET代谢的主要途径。然而，当人冠状动脉内皮细胞（HCEC）与3 H-标记的14，15-EET孵育时，链缩短的环氧脂肪酸，而不是DHET，是最丰富的代谢产物。孵育4小时后，培养基中剩余的总放射性的23%转化为10，11-环氧-十六碳二烯酸（16：2），这是14，15-EET通过两个β-氧化循环形成的产物，而仅15%以14，15-DHET形式存在。虽然大量存在于培养基中，但在细胞脂质中未检测到10，11-环氧-16：2。外源性H-3标记的10，11-epoxy-16：2既不代谢也不保留在细胞中，表明10，11-epoxy-16：2是HCEC中14，15 EET代谢的主要产物。10，11-环氧-16：2在冠状动脉微血管中产生有效的扩张。10，11-Epoxy-16：2还有效抑制肿瘤坏死因子-α诱导的HCEC产生IL-8（一种促炎细胞因子）。这些发现暗示β-氧化是HCEC中14，15-EET代谢的主要途径，并提供了EET衍生的短链环氧脂肪酸具有生物活性的第一个证据。
Cytochrome P-450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) play an important role in the regulation of vascular reactivity and function. Conversion to the corresponding dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolases is thought to be the major pathway of EET metabolism in mammalian vascular cells. However, when human coronary artery endothelial cells (HCEC) were incubated with 3 H-labeled 14,15-EET, chain-shortened epoxy fatty acids, rather than DHET, were the most abundant metabolites. After 4 h of incubation, 23% of the total radioactivity remaining in the medium was converted to 10,11-epoxy-hexadecadienoic acid (16:2), a product formed from 14,15-EET by two cycles of beta-oxidation, whereas only 15% was present as 14,15-DHET. Although abundantly present in the medium, 10,11-epoxy-16:2 was not detected in the cell lipids. Exogenously applied H-3-labeled 10,11-epoxy-16:2 was neither metabolized nor retained in the cells, suggesting that 10,11-epoxy-16:2 is a major product of 14,15EET metabolism in HCEC. 10,11-Epoxy-16:2 produced potent dilation in coronary microvessels. 10,11-Epoxy-16:2 also potently inhibited tumor necrosis factor-alpha-induced production of IL-8, a proinflammatory cytokine, by HCEC. These findings implicate beta-oxidation as a major pathway of 14,15-EET metabolism in HCEC and provide the first evidence that EET-derived chain-shortened epoxy fatty acids are biologically active.