CYP2J2 targeting to endothelial cells attenuates adiposity and vascular dysfunction in mice fed a high-fat diet by reprogramming adipocyte phenotype.
CYP2J2 targeting to endothelial cells attenuates adiposity and vascular dysfunction in mice fed a high-fat diet by reprogramming adipocyte phenotype.
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DOI：
10.1161/hypertensionaha.114.03884
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Schwartzman ML
中科院分区：
文献类型：
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作者：
Abraham NG;Sodhi K;Silvis AM;Vanella L;Favero G;Rezzani R;Lee C;Zeldin DC;Schwartzman ML
肥胖是一种全球流行病，是内皮功能障碍以及随后发展为糖尿病和高血压等血管疾病的常见危险因素。环氧二十碳三烯酸(EETs)是由细胞色素P450衍生的花生四烯酸(AA)的代谢物，通过刺激血管扩张和抑制炎症而有助于血管保护。血红素氧合酶-1(HO-1)是一种应激反应蛋白，在糖尿病和心血管疾病中对氧化损伤具有重要的细胞保护作用。我们最近证实了EETs和HO-1在抑制脂肪生成中的相互作用。我们研究了喂食高脂肪(HF)饮食的小鼠的脂肪细胞功能障碍是否可以通过内皮特异性靶向人类CYP环氧合酶，CYP2J2来预防。服用HF饮食的转基因小鼠体重增加、血糖、胰岛素水平和炎症标记物水平降低。Tie2-CYP2J2基因打靶修复了HF介导的血管HO-1、Cyp2C44、sEH、PENOS、PAKT和pAMPK蛋白的表达，从而改善血管功能。这些变化表现为脂肪组织内炎症和氧化应激的减少，以及PPARγ、C/EBPα、Mest和AP2的表达降低，UCP1和UCP2的表达增加，反映了血管内皮细胞过度分泌对脂肪形成的影响。目前的研究证明了内皮特异性EET的产生和脂肪形成之间的直接联系，进一步表明EET-HO-1串扰在改善饮食诱导的肥胖引起的血管和脂肪细胞功能障碍方面是一个重要的细胞保护机制。
Obesity is a global epidemic and a common risk factor for endothelial dysfunction, and the subsequent development of diabetes and vascular diseases such as hypertension. Epoxyeicosatrienoic acids (EETs) are CYP450-derived metabolites of arachidonic acid (AA) that contribute to vascular protection by stimulating vasodilation and inhibiting inflammation. Heme oxygenase-1 (HO-1) is a stress response protein that plays an important cytoprotective role against oxidative insult in diabetes and cardiovascular disease. We recently demonstrated interplay between EETs and HO-1 in the attenuation of adipogenesis. We examined whether adipocyte dysfunction in mice fed a high fat (HF) diet could be prevented by endothelial-specific targeting of the human CYP epoxygenase, CYP2J2. Tie2-CYP2J2 transgenic mice, fed a HF diet, had a reduction in body weight gain, blood glucose, insulin levels and inflammatory markers. Tie2-CYP2J2 gene targeting restored HF-mediated decreases in vascular HO-1, Cyp2C44, sEH, peNOS, pAKT, and pAMPK protein expression, thus improving vascular function. These changes translated into decreased inflammation and oxidative stress within adipose tissue and decreased PPARγ, C/EBPα, Mest, and aP2 expression and increased UCP1 and UCP2 expression, reflecting the effect of vascular EET overproduction on adipogenesis. The current study documents a direct link between endothelial-specific EET production and adipogenesis, further implicating the EET-HO-1 crosstalk as an important cytoprotective mechanism in the amelioration of vascular and adipocyte dysfunction resulting from diet-induced obesity.