MECHANISM OF DISEASE PREVENTION BY N 3 FATTY ACIDS

N 3 脂肪酸的防病机制

• 批准号: 2882762
• 负责人: ALEXANDER LEAF
• 金额: $ 28.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2882762
• 关键词: antiarrhythmic agent; calcium flux; cardiovascular disorder prevention; chemical structure function; dietary lipid; eicosanoid metabolism; eicosanoids; fatty acid analog; heart cell; laboratory rat; lipid structure; lysolecithins; membrane channels; membrane lipids; nutrition related tag; omega 3 fatty acid; phospholipids; tissue /cell culture; unsaturated fatty acids; voltage /patch clamp

Our broad, long term objective is to understand the mechanism(s) by which common dietary polyunsaturated fatty acids (PUFA) can prevent lethal cardiac tachyarrhythmias resulting from ischemic, toxic, hormonal, or neurohumoral stress, as we now have demonstrated. Of the dietary PUFAs two omega-3 (n-3) PUFA, eicosapentaenoic acid (C2O:5n-3, EPA) and docosahexaenoic (c22:6n-3) are the most potent in their antiarrhythmic effects, whereas arachidonic acid (C2O:4n-3, AA) is proarrhythmic if the heart cells are making ecoisanoids from AA. Our specific aims are: (1) To determine if the primary source of the free PUFA which prevents cardiac arrhythmias is that PUFA occupying the sn-2 position in membrane phospholipids or that in the nonesterified fatty acid pool. (2) To determine if there exists a relationship between the potent dysrhythmic effects of lysophosphatidylcholine and the prevention of that arrhythmia by PUFA (3) To determine which eicosanoid (oxidized metabolite) of AA is prodysrhythmic, i.e., an AA product of cyclooxygenase, lipoxygenase, or epoxygenase, and what is the mechanism of its arrhythmic effect. (4) To determine cytosolic free Ca2+ levels when PUFA inhibit dysrhythmias. (5) To determine by patch clamp which ion channel(s) is modulated to make the changes in excitability/automaticity which EPA and DHA produce in isolated heart cells. These changes, we now think, constitute the primary antiarrhythmic action of these PUFAs. The health relatedness of these studies is that they will increase our understanding of how these fatty acids, when ingested chronically in the diet or injected intraveneously just prior to an ischemic stress can prevent fatal arrhythmias. With some 60% of deaths (some 300,000 annually) from acute myocardial infarctions resulting from sudden cardiac death, i.e., ventricular tachyarrhythmias, in the U.S.A., the potential public health benefits of this knowledge may be considerable.

我们广泛的长期目标是了解 常见的膳食多不饱和脂肪酸（PUFA）可以防止致命的 缺血性、毒性、激素或 神经体液应激，正如我们现在所证明的。在膳食PUFA中， ω-3（n-3）PUFA、二十碳五烯酸（C2 O：5 n-3，EPA）和 二十二碳六烯酸（C22：6 N-3）在其抗肿瘤作用中是最有效的 作用，而花生四烯酸（C2 O：4 n-3，AA）是promammic，如果 心脏细胞从AA中合成类花生四烯酸。 我们的具体目标是： (1)为了确定是否游离PUFA的主要来源， 心律失常是PUFA占据膜上的sn-2位置 磷脂或非酯化脂肪酸池中的脂肪酸。 (2)以确定是否存在一种关系， 溶血磷脂酰胆碱的节律紊乱作用及其预防 PUFA心律失常 (3)为了确定AA的哪种类二十烷酸（氧化代谢物） 前节律紊乱，即，环氧合酶、脂氧合酶的AA产物，或 环氧合酶，以及它的药理作用机制是什么。 (4)测定PUFA抑制时细胞内游离Ca 2+水平 心律失常 (5)通过膜片钳确定哪个或哪些离子通道被调节， EPA和DHA产生的兴奋性/自动性的变化， 分离的心脏细胞我们现在认为，这些变化构成了 这些PUFA的抗肿瘤作用。 这些研究的健康相关性在于，它们将增加我们的 了解这些脂肪酸，当摄入长期在 在缺血性应激之前进行饮食或静脉内注射可 预防致命的心律失常。约60%的死亡（每年约30万人） 由心脏性猝死引起的急性心肌梗塞， 也就是说，室性快速性心律失常，在美国，潜在的公共 这些知识对健康的好处可能是相当大的。

项目成果

Partitioning of polyunsaturated fatty acids, which prevent cardiac arrhythmias, into phospholipid cell membranes.

将防止心律失常的多不饱和脂肪酸分配到磷脂细胞膜中。

• 发表时间: 2001
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: Pound,EM;Kang,JX;Leaf,A
• 通讯作者: Leaf,A

Characterization of several phospholipase activities and diacylglycerol/2-monoacylglycerol lipases in rat alveolar macrophages.

大鼠肺泡巨噬细胞中几种磷脂酶活性和二酰基甘油/2-单酰基甘油脂肪酶的表征。

• DOI: 10.1016/0005-2760(91)90095-y
• 发表时间: 1991
• 期刊: Biochimica et biophysica acta
• 作者: Errasfa,M

1 alpha,25-(OH)2 vitamin D3 enhances expression of the genes encoding Ca(2+)-binding proteins MRP-8 and MRP-14.

1 α,25-(OH)2 维生素 D3 增强编码 Ca(2) 结合蛋白 MRP-8 和 MRP-14 的基因表达。

• DOI: 10.1152/ajpcell.1992.262.1.c235
• 发表时间: 1992
• 期刊: The American journal of physiology
• 作者: Sellmayer,A;Krane,SM;Ouellette,AJ;Bonventre,JV
• 通讯作者: Bonventre,JV

Omega 3 polyunsaturated fatty acid modulates dihydropyridine effects on L-type Ca2+ channels, cytosolic Ca2+, and contraction in adult rat cardiac myocytes.

Omega 3 多不饱和脂肪酸调节二氢吡啶对 L 型 Ca2 通道、胞质 Ca2 和成年大鼠心肌细胞收缩的影响。

• DOI: 10.1073/pnas.91.19.8832
• 发表时间: 1994
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Pepe,S;Bogdanov,K;Hallaq,H;Spurgeon,H;Leaf,A;Lakatta,E
• 通讯作者: Lakatta,E

Cardiovascular effects of omega 3 fatty acids. Atherosclerosis risk factor modification by omega 3 fatty acids.

欧米伽 3 脂肪酸对心血管的影响。

• 发表时间: 1991
• 期刊: World review of nutrition and dietetics
• 作者: Weber,PC;Leaf,A
• 通讯作者: Leaf,A