CYP2J3 Gene Delivery Reduces Insulin Resistance via Upregulation of eNOS in Fructose-treated Rats
CYP2J3 Gene Delivery Reduces Insulin Resistance via Upregulation of eNOS in Fructose-treated Rats
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CYP2J3 基因传递通过上调 eNOS 降低果糖治疗大鼠的胰岛素抵抗
DOI：
10.1186/1475-2840-10-114
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发表时间：
2011-12-21
影响因子：
9.3
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
--
作者：
Xu, Xizhen;Tu, Ling;Wang, Dao Wen
越来越多的证据表明，细胞色素 P450 (CYP) 环氧化酶将花生四烯酸代谢为环氧二十碳三烯酸 (EET)，后者在各种病理生理过程中发挥重要作用。有趣的是，CYP 衍生的类二十烷酸具有血管舒张作用，至少部分是通过其激活 eNOS 和随后释放 NO 的能力实现的。本研究调查了 eNOS 在 CYP2J3 基因传递中的作用，从而降低果糖治疗大鼠的血压和改善胰岛素抵抗。根据胰岛素抵抗指数 (HOMA-IR) 的测定，体内 CYP2J3 过表达会增加 EET 生成、降低血压并逆转胰岛素抵抗。此外，eNOS抑制剂L-NMMA的施用显着且部分消除了CYP2J3基因递送对果糖摄入引起的高血压和胰岛素抵抗的有益作用，其可能的机制与ET-1、ETA受体mRNA表达增加以及胰岛素对外周组织和器官的敏感性降低有关，其特征在于IRS-1/PI3K/AKT和AMPK信号通路活性降低。这些数据提供了直接证据，表明 CYP2J3 衍生的 EET 可能至少部分通过上调 eNOS 表达来减轻胰岛素抵抗。
Accumulating evidence suggests that cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs) which play important roles in various pathophysiological processes. Interestingly, CYP-derived eicosanoids are vasodilatory, at least in part through their ability to activate eNOS and subsequent NO release. This study investigated the roles of eNOS in CYP2J3 gene delivery reducing blood pressure and improving insulin resistance in fructose-treated rats. CYP2J3 overexpression in vivo increased EET generation, reduced blood pressure and reversed insulin resistance as determined by insulin resistance index (HOMA-IR). Furthermore, administration of eNOS inhibitor L-NMMA significantly and partially abolished the beneficial effects of CYP2J3 gene delivery on hypertension and insulin resistance induced by fructose intake, and possible mechanism is associated with increased ET-1, ETA-receptor mRNA expression and reduced sensitivity of insulin to peripheral tissues and organs characterized by reduced activity of IRS-1/PI3K/AKT and AMPK signalling pathways. These data provide direct evidence that CYP2J3-derived EETs may alleviate insulin resistance at least in part through upregulated eNOS expression.