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Aspirin and lipid mediators in the cardiovascular system

机译:阿司匹林和脂质介质在心血管系统中的作用

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Aspirin is an unique compound because it bears two active moieties within one and the same molecule: a reactive acetyl group and the salicylate metabolite. Salicylate has some effects similar to aspirin, however only at higher concentrations, usually in the millimolar range, which are not obtained at conventional antiplatelet aspirin doses of 100-300 mg/day. Pharmacological actions of aspirin in the cardiovascular system at these doses are largely if not entirely due to target structure acetylation. Several classes of lipid mediators become affected: Best known is the cyclooxygenase-1 (COX-1) in platelets with subsequent inhibition of thromboxane and, possibly, thrombin formation. By this action, aspirin also inhibits paracrine thromboxane functions on other lipid mediators, such as the plateletstorage product sphingosine-1-phosphate (S1P), an inflammatory mediator. Acetylation of COX-2 allows for generation of 15-(R)HETE and subsequent formation of "aspirin-triggered lipoxin" (ATL) by interaction with white cell lipoxygenases. In the cardiovascular system, aspirin also acetylates eNOS with subsequent upregulation of NO formation and enhanced expression of the antioxidans heme-oxygenase-1. This action is possibly also COX-2/ATLmediated. Many more acetylation targets have been identified in live cells by quantitative acid-cleavable activity-based protein profiling and might result in discovery of even more aspirin targets in the near future. (c) 2015 Elsevier Inc. All rights reserved.
机译:阿司匹林是一种独特的化合物,因为它在一个相同的分子内带有两个活性部分:一个反应性乙酰基和水杨酸酯代谢物。水杨酸盐具有一些与阿司匹林相似的作用,但是仅在较高浓度下(通常在毫摩尔范围内),而在常规抗血小板阿司匹林剂量为100-300 mg / day时则无法获得。这些剂量下的阿司匹林在心血管系统中的药理作用很大程度上(如果不是全部)归因于靶标结构乙酰化。几类脂质介体受到影响:最著名的是血小板中的环氧合酶1(COX-1),随后会抑制血栓烷,并可能抑制凝血酶的形成。通过这种作用,阿司匹林还可以抑制旁分泌血栓烷对其他脂质介体的功能,例如血小板储存产物1磷酸鞘氨醇(S1P)(一种炎症性介体)。通过与白细胞脂氧合酶的相互作用,COX-2的乙酰化可以生成15-(HE)HETE,并随后形成“阿司匹林触发的脂蛋白”(ATL)。在心血管系统中,阿司匹林还可以使eNOS乙酰化,进而上调NO的形成并增强抗氧化血红素加氧酶-1的表达。此动作也可能是COX-2 / ATL介导的。通过定量的酸可裂解的基于活性的蛋白质谱分析,已经在活细胞中鉴定出了更多的乙酰化靶标,并可能在不久的将来发现更多的阿司匹林靶标。 (c)2015 Elsevier Inc.保留所有权利。

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