A potent soluble epoxide hydrolase inhibitor, t-AUCB, acts through PPARγ to modulate the function of endothelial progenitor cells from patients with acute myocardial infarction.
A potent soluble epoxide hydrolase inhibitor, t-AUCB, acts through PPARγ to modulate the function of endothelial progenitor cells from patients with acute myocardial infarction.
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DOI：
10.1016/j.ijcard.2012.03.167
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发表时间：
2013-08-20
影响因子：
3.5
通讯作者：
Hammock, Bruce D.
中科院分区：
文献类型：
--
作者：
Xu, Dan-yan;Davis, Benjamin B.;Wang, Zhen-he;Zhao, Shui-ping;Wasti, Binaya;Liu, Zhe-liang;Li, Ning;Morisseau, Christophe;Chiamvimonvat, Nipavan;Hammock, Bruce D.
关键词：
环氧二十碳三烯酸 (EET) 是受可溶性环氧化物水解酶 (sEH) 调节的天然血管生成介质。 sEH 抑制剂可以稳定 EET 水平，据报道可以在动物模型中减少动脉粥样硬化并抑制心肌梗塞。在这项工作中，我们研究了使用 sEH 抑制剂 t-AUCB 增加 EET 是否会增加急性心肌梗死 (AMI) 患者内皮祖细胞 (EPC) 的血管生成相关功能。从 50 名 AMI 患者和 50 名健康受试者（对照）中分离出 EPC。用不同浓度的 t-AUCB 在有或没有过氧化物酶体增殖物激活受体 γ (PPARγ) 抑制剂 GW9662 的情况下处理 EPC 24 小时。 EPC 的迁移在跨孔室中进行测定。使用基质胶-基质体外模型进行血管生成测定。实时荧光定量PCR或Western blot分别检测EPCs中血管内皮生长因子（VEGF）、缺氧诱导因子1α（HIF-1α）mRNA和蛋白的表达。另外，通过ELISA检测培养上清液中的EET浓度。与健康对照组相比，AMI 患者组的 EPC 活性降低。而用 t-AUCB 提高 EET 水平可促进 AMI 患者 EPC 的剂量依赖性血管生成和迁移。此外，t-AUCB 剂量依赖性地增加血管生成因子 VEGF 和 HIF-α 的表达。最后，我们证明这些效应是 PPARγ 依赖性的。结果表明，sEH抑制剂通过EETs-PPARγ途径正向调节AMI患者EPCs的功能。本研究表明 sEHi 在治疗缺血性心脏病中的潜在用途。
Epoxyeicosatrienoic acids (EETs) are natural angiogenic mediators regulated by soluble epoxide hydrolase (sEH). Inhibitors of sEH can stabilize EETs levels and were reported to reduce atherosclerosis and inhibit myocardial infarction in animal models. In this work, we investigated wether increasing EETs with the sEH inhibitor t-AUCB would increase angiogenesis related function in endothelial progenitor cells (EPCs) from patients with acute myocardial infarction (AMI). EPCs were isolated from 50 AMI patients and 50 healthy subjects (control). EPCs were treated with different concentrations of t-AUCB for 24 hours with or without peroxisome proliferator activated receptor γ (PPARγ) inhibitor GW9662. Migration of EPCs was assayed in trans-well chambers. Angiogenesis assays were performed using a Matrigel-Matrix in vitro model. The expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α) mRNA and protein in EPCs were measured by real-time PCR or Western blot, respectively. Also, the concentration of EETs in the culture supernatant was detected by ELISA. The activity of EPCs in the AMI patient group was reduced compared to healthy controls. Whereas increasing EET levels with t-AUCB promoted a dose dependent angiogenesis and migration in EPCs from AMI patients. Additionally, the t-AUCB dose dependently increased the expression of the angiogenic factors VEGF and HIF-α. Lastly, we showed that these effects were PPARγ dependent. The results demonstrate that the sEH inhibitor positively modulated the functions of EPCs in patients with AMI through the EETs-PPARγ pathway. The present study suggests the potential utility of sEHi in the therapy of ischemic heart disease.
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影响因子：
5
作者：
Jujo, Kentaro;Ii, Masaaki;Losordo, Douglas W.
通讯作者：
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影响因子：
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影响因子：
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Hwang, Sung Hee;Tsai, Hsing-Ju;Hammock, Bruce D.
通讯作者：
Hammock, Bruce D.