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首页> 外文期刊>Prostaglandins and Other Lipid Mediators >Effect of human 15-lipoxygenase-l metabolites on vascular function in mouse mesenteric arteries and hearts
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Effect of human 15-lipoxygenase-l metabolites on vascular function in mouse mesenteric arteries and hearts

机译:人15脂氧合酶-1代谢产物对小鼠肠系膜动脉和心脏血管功能的影响

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Lipoxygenases regulate vascular function by metabolizing arachidonic acid (AA) to dilator eicosanoids. Previously, we showed that endothelium-targeted adenoviral vector-mediated gene transfer of the human 15-lipoxygenase-l (h15-LO-l) enhances arterial relaxation through the production of vasodila-tory hydroxyepoxyeicosatrienoic acid (HEETA) and trihydroxyeicosatrienoic acid (THETA) metabolites. To further define this function, a transgenic (Tg) mouse line that overexpresses h1 5-LO-l was studied. Western blot, immunohistochemistry and RT-PCR results confirmed expression of 15-LO-l transgene in tissues, especially high quantity in coronary arterial wall, of Tg mice. Reverse-phase HPLC analysis of [14C]-AA metabolites in heart tissues revealed enhanced 15-HETE synthesis in Tg vs. WT mice. Among the 15-LO-l metabolites, 15-HETE, erythro-13-H-14,15-EETA, and 11(R),12(S),15(S)-THETA relaxed the mouse mesenteric arteries to the greatest extent. The presence of h15-LO-l increased acetylcholine-and AA-mediated relaxation in mesenteric arteries of Tg mice compared to WT mice. 15-LO-l was most abundant in the heart; therefore, we used the Langendorff heart model to test the hypothesis that elevated 15-LO-l levels would increase coronary flow following a short ischemia episode. Both peak flow and excess flow of reperfused hearts were significantly elevated in hearts from Tg compared to WT mice being 2.03 and 3.22 times greater, respectively. These results indicate that h15-LO-l -derived metabolites are highly vasoactive and may play a critical role in regulating coronary blood flow.
机译:脂氧合酶通过将花生四烯酸(AA)代谢为扩张型二十烷酸来调节血管功能。以前,我们表明人15脂氧合酶-1(h15-LO-1)的靶向内皮的腺病毒载体介导的基因转移通过产生血管舒张性羟基环氧二十碳三烯酸(HEETA)和三羟基二十碳三烯酸(THETA)增强动脉松弛代谢产物。为了进一步定义该功能,研究了过表达h1 5-LO-1的转基因(Tg)小鼠品系。 Western印迹,免疫组织化学和RT-PCR结果证实了15-LO-1转基因在Tg小鼠的组织中表达,特别是在冠状动脉壁中的大量表达。心脏组织中[14C] -AA代谢物的反相HPLC分析显示,Tg与WT小鼠相比15-HETE合成增强。在15-LO-1代谢产物中,15-HETE,erythro-13-H-14,15-EETA和11(R),12(S),15(S)-THETA使小鼠肠系膜动脉最大程度地松弛程度。与WT小鼠相比,h15-LO-1的存在增加了Tg小鼠的肠系膜动脉中乙酰胆碱和AA介导的松弛。 15-LO-1在心脏中含量最高;因此,我们使用Langendorff心脏模型来检验以下假设:短暂的缺血发作后15-LO-1水平升高会增加冠状动脉血流量。与WT小鼠相比,来自Tg的心脏的再灌注心脏的峰值流量和过量流量均显着升高,分别是WT小鼠的2.03倍和3.22倍。这些结果表明,h15-LO-1衍生的代谢产物具有高度血管活性,并且可能在调节冠状动脉血流中起关键作用。

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