Activation of peroxisome proliferator-activated receptor α by substituted urea-derived soluble epoxide hydrolase inhibitors
Activation of peroxisome proliferator-activated receptor α by substituted urea-derived soluble epoxide hydrolase inhibitors
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DOI：
10.1124/jpet.105.085605
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发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Spector, AA
中科院分区：
文献类型：
--
作者：
Fang, X;Hu, SM;Spector, AA
可溶性环氧化物水解酶(SEH)在调节血管环氧二十碳三烯酸的代谢和功能中起着重要作用，抑制sEH活性的取代尿素类化合物可降低高血压大鼠的血压。我们发现，含有十二酸基团的取代尿素衍生物，除了有效地抑制sEH外，还能增加PPARα的活性。在转导PPARα的COS-7细胞中，10 mU M-N-环己基-N‘-十二烷酸脲(CUDA)或N-金刚烷基-N’-十二酸脲(AudA)分别使PPARα的激活增加6倍和3倍。CUDA和AUDA都没有直接激活PPAR增量或PPAR伽马，这表明对PPARα具有选择性。CudA不改变PPARα蛋白的表达，它竞争性地抑制Wy-14643(吡尼昔酸)与PPARα的配体结合域的结合，表明它是PPARα的配体。Cuda和Auda被代谢成链缩短的β-氧化产物，这一过程降低了它们作为sEH抑制剂的效力，以及它们结合和激活PPARα的能力。N，N‘-二环己基脲和N-环己基-N’-十二烷基脲是不含羧基的sEH抑制剂，不能激活PPARα。在HepG2细胞中，CUDA增加了PPARα反应基因肉碱棕榈酰基转移酶1A的表达。我们的结论是，CUDA和AudA通过其羧酸取代，除了有效地抑制sEH外，还激活PPARα。这些化合物的进一步开发可能导致一类具有降压和降脂特性的药物，这些药物可能对心血管疾病的预防和治疗有价值。
Soluble epoxide hydrolase (sEH) plays a major role in regulating vascular epoxyeicosatrienoic acid metabolism and function, and substituted urea derivatives that inhibit sEH activity reduce blood pressure in hypertensive rats. We found that substituted urea derivatives containing a dodecanoic acid group, besides effectively inhibiting sEH, increased peroxisome proliferator-activated receptor ( PPAR) alpha activity. In PPAR alpha transfected COS-7 cells, treatment with 10 mu M N-cyclohexyl-N'-dode-canoic acid urea (CUDA) or N-adamantanyl-N'-dodecanoic acid urea (AUDA) produced 6- and 3-fold increases, respectively, in PPAR alpha activation. Neither CUDA nor AUDA activated PPAR delta or PPAR gamma directly, indicating selectivity for PPAR alpha. CUDA did not alter PPAR alpha protein expression, and it competitively inhibited the binding of Wy-14643 (pirinixic acid) to the ligand binding domain of PPAR alpha, suggesting that it functions as a PPAR alpha ligand. CUDA and AUDA were metabolized to chain-shortened beta-oxidation products, a process that reduced their potency as sEH inhibitors and their ability to bind and activate PPAR alpha. N, N'-Dicylclohexylurea and N-cyclohexyl- N'-dodecylurea, sEH inhibitors that do not contain a carboxylic acid group, did not activate PPAR alpha. In HepG2 cells, CUDA increased the expression of the PPAR alpha-responsive gene carnitine palmitoyltransferase 1A. We conclude that CUDA and AUDA, by virtue of their carboxylic acid substitution, activate PPAR alpha in addition to potently inhibiting sEH. Further development of these compounds could lead to a class of agents with hypotensive and lipid-lowering properties that may be valuable for the prevention and treatment of cardiovascular disease.