HOW DIETARY N-3 FATTY ACIDS PREVENT FATAL ARRHYTHMIAS

膳食 N-3 脂肪酸如何预防致命性心律失常

• 批准号: 6390279
• 负责人: ALEXANDER LEAF
• 金额: $ 24.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390279
• 关键词: action potentials; antiarrhythmic agent; arrhythmia; cardiac myocytes; cell line; chemoprevention; dietary lipid; drug receptors; heart electrical activity; laboratory rat; local anesthetics; marine animal oil; membrane potentials; myocardial ischemia /hypoxia; nutrition related tag; omega 3 fatty acid; sodium channel; sudden cardiac death; tissue /cell culture; transfection; voltage /patch clamp; voltage gated channel

Specific Aims: We have shown that the n-3 polyunsaturated fatty acids (PUFAs) in fish oils, which prevent sudden cardiac death, like local anesthetics, inhibit the fast, voltage dependent Na+ currents (i.e., a voltage-dependent need for a more negative resting membrane potential to close and return the Na+ channels to a resting, activatable state). Aim 1. Too determine if the voltage sensitivity of this effect is sufficient to inhibit action potentials in partially depolarized zones of the heart, but not affect non-ischemic cardiomyocytes that retain their normal resign membrane potentials. If so, this could explain the role of the inhibition of INa by n-3 PUFAS in ischemia-induced sudden cardiac death. Aim 2. To determine in a human embryonic cell line, HEK 293t, expressing alpha-subunits of the human myocardial sodium channel (hH1alpha), if point amino acid mutations in D-1, S6- the location of the putative batrachotoxin (BTX) binding site- and D-IV, S6- the location of the putative local anesthetic (LA) receptor-block the action of the n-3PUFAs on the Na+ channel grating process. Similarities between effects of Las and n-3 PUFAs indicates this to be likely: a) Both displace BTX, a potent cardiac and neural poison, from its binding site on the activated state of the Na+ channel alpha- subunit by non-competitive inhibition. B) Both inhibit INa by prolonging the inactivated state of the Na+ channel. C) Both are potent anti-arrhythmic agents. D-IV, S6 is the putative site of the LA receptor an D-I, S6 is the site of BTX binding. A single amino acid mutation in these two regions of the alpha-subunit renders the channel insensitive to BTX and affect LA action on the Na channel. These studies will add to understanding of how n-3 PUFAs act at a molecular level to inhibit the INa in cardiac myocytes. This effect is important for the preention by these n-3 PUFAs of ischemia-induced fatal ventricular arrhythmias. With 250,000 Americans, and millions more world wide, dying annually from cardiac sudden death for which there is no current safe and effective prevention or therapy, this action of the PUFAs has potentially great public health benefit.

具体目标：我们已经表明，鱼油中的n-3多不饱和脂肪酸（PUFA），如局部麻醉剂，可以防止心脏猝死，抑制快速的电压依赖性Na+电流（即，电压依赖性地需要更负的静息膜电位以关闭Na+通道并使其返回到静息的可激活状态）。目标1。也确定这种效应的电压敏感性是否足以抑制心脏部分去极化区的动作电位，但不影响保持其正常重膜电位的非缺血性心肌细胞。如果是这样的话，这可以解释n-3 PUFAS抑制INa在缺血诱导的心脏性猝死中的作用。目标2. 为了确定在表达人心肌钠通道α亚单位（hH 1 α）的人胚胎细胞系HEK 293 t中，D-1、S6（推定的蟾毒素（BTX）结合位点的位置）和D-IV、S6（推定的局部麻醉剂（LA）受体的位置）中的点氨基酸突变是否阻断n-3 PUFA对Na+通道光栅过程的作用。Las和n-3 PUFA作用之间的相似性表明这是可能的：a）两者都通过非竞争性抑制将BTX（一种强效心脏和神经毒物）从其在Na+通道α亚基激活状态上的结合位点上取代。B）两者均通过延长Na+通道的失活状态来抑制INa。C）两者都是有效的抗肿瘤剂。D-IV，S6是LA受体的推定位点，D-I，S6是BTX结合位点。在α-亚基的这两个区域中的单个氨基酸突变使得通道对BTX不敏感并影响LA对Na通道的作用。这些研究将有助于了解n-3 PUFA如何在分子水平上抑制心肌细胞中的INa。这种作用对于这些n-3 PUFA预防缺血诱导的致命性室性心律失常是重要的。每年有250，000名美国人和全世界数百万人死于心脏性猝死，目前没有安全有效的预防或治疗方法，PUFA的这种作用具有潜在的巨大公共卫生益处。