MECHANISMS OF DISEASE PREVENTION BY N-3 FATTY ACIDS

本研究的目的是了解鱼油脂肪的作用机制。 酸可以影响细胞对正常激动剂和有毒物质的反应 探员们。有充分的证据表明，长链多不饱和n-3或 N-6脂肪酸(PUFA)对许多细胞过程有不同的影响。 含有鱼或鱼油的饮食会改变一些炎症、免疫性、 和动脉粥样硬化的过程。这些影响可能是由于 二十碳二烯、二十二碳二烯、白三烯、脂蛋白或P450的差异 二十碳五烯酸产生的代谢物，EPA(C20：5N-3)，以及 二十二碳六烯酸，DHA(C22：6N-3)，当它们取代花生四烯酸时， 膜磷脂sn-2位的氨基酸(C20：4n-6)。 或者，它们可能直接归因于 膜结合蛋白(酶、受体、运输通道) 这是由于它们的磷脂微环境中含有EPA和DHA。 这些细微的变化是如何引起细胞功能的变化的 磷脂脂肪酸还不是很清楚。 我们已经证明，用EPA或DHA丰富分离的大鼠心肌细胞 (与n-6氨基酸相反)在体外完全保护心肌细胞 高浓度强心苷(10-4M哇巴因)的毒性。 EPA或DHA可防止致死水平的胞浆钙对有毒物质的反应 哇巴因通过阻断钙离子进入心肌细胞而浓缩。 这种保护作用的机制可以通过进一步的研究来阐明。 在我们的模型系统中。 在美国每年死于心脏病发作的50万人中 在受害者被送往医院之前，将有30万人死亡， 根据美国心脏协会的数据。其中绝大多数都是 “猝死”是由室颤引起的。因此，我们的研究要 了解鱼油脂肪酸防止 心肌细胞心律失常可能具有潜在的公共健康 重要性。

The object of this study is to learn the mechanisms by which fish oil fatty acids can affect the responses of cells to normal agonists and noxious agents. There is ample evidence that the long chain polyunsaturated n-3 or n-6 fatty acids (PUFA) can affect differently many cellular processes. Diets containing fish or fish oils alter some inflammatory, immunologic, and atherosclerotic processes. These effects could be due to the differences in eicosanoids, docosanoids, leukotrienes, lipoxins, or P450 metabolites produced from eicosapentaenoic acid, EPA (C20:5n-3), and docosahexaenoic acid, DHA (C22:6n-3), when they replace arachidonic acid, AA (C20:4n-6) in the sn-2 position of membrane phospholipids. Alternatively, they could be due directly to changes in the function of membrane-bound proteins (enzymes, receptors, transport channels) resulting from enrichment of their phospholipid microenvironment with EPA and DHA. How changes in cellular functions are induced by these subtle changes of phospholipid fatty acids is not yet understood. We have shown that enriching isolated rat cardiac myocytes with EPA or DHA (in contrast to n-6 AA) in vitro completely protects the myocytes against toxicity from a high concentration of cardiac glycosides (10-4 M ouabain). EPA or DHA prevents lethal levels of cytosolic calcium in response to toxic concentrations of ouabain by blocking entry of calcium into the myocytes. The mechanism of this protective effect can be clarified by further studies in our model systems. Of the half million deaths from heart attacks annually in the United States, 300,000 deaths will occur before the victims get to a hospital, according to the American Heart Association. The great majority of these "sudden deaths" are due to ventricular fibrillation. Thus our studies to understand the mechanisms by which the fish oil fatty acids prevent arrhythmias of cardiac myocytes may have potential public health importance.