A PUFA Dietary Intervention for Heart Rate

PUFA 饮食干预心率

• 批准号: 8552336
• 负责人: Edward Lakatta
• 金额: $ 29.25万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552336
• 关键词: 4 hydroxynonenal; Acids; Affect; Affinity; Age; Alzheimer' s Disease; Animals; Aorta; Arrhythmia; Behavior; Calcium; Cardiac; Cardiolipins; Cardiovascular system; Categories; Caveolins; Cells; Cellular Membrane; Ceramides; Cessation of life; Chemistry; Cholesterol; Clinical; Complex; Connexin 43; Control Animal; Data; Data Analyses; Diet; Dietary Intervention; Disease; Elderly; Enzymes; Epidemiologic Studies; Epidemiology; Esters; Event; Fatty Acids; Fatty acid glycerol esters; Fish Oils; Fishes; Gangliosides; Gas Chromatography; Heart; Heart Atrium; Heart Rate; Heart failure; Homeostasis; Image; Individual; Industry; Ion Channel; Ions; Link; Lipid Peroxidation; Lipids; Mediator of activation protein; Membrane; Membrane Lipids; Membrane Microdomains; Methodology; Mitochondrial Proteins; Modeling; Mole the mammal; Nerve; Nodal; Omega-3 Fatty Acids; Organizational Change; Oryctolagus cuniculus; Outcome; Outcome Study; Oxidation-Reduction; Pacemakers; Pharmaceutical Preparations; Polyunsaturated Fatty Acids; Property; Proteins; Protocols documentation; Rattus; Residual state; Rest; Rodent; Sarcoplasmic Reticulum; Signal Transduction; Signaling Molecule; Signaling Protein; Sinoatrial Node; Skin; Sphingomyelins; Surface; Tissues; Ultracentrifugation; Ventricular; Ventricular Fibrillation; age related; arm; normal aging; novel; patch clamp; protein distribution

We, and others, have demonstrated that dietary content of long chain polyunsaturated fatty acids (PUFA) affects their incorporation into cell membrane lipid rafts. Mechanisms underlying the effect of PUFAs include changes in release of bioactive mediators, ion channel activity and cellular membrane behavior. PUFA have a dramatic impact on cell ion homeostasis and redox chemistry. Omega 3 PUFA, the good variety of PUFA, type typified by Docosohexanoic acid, protect from lethal post-ischemic arrhythmias, whilst the Omega 6, the bad variety of PUFA, promote theses arrhythmias. With advancing age in rodents, membrane Omega 3 decrease and Omega 6 increase. Old rats are extremely vulnerable to post ischemic ventricular fibrillation. The age-associated change in membrane PUFA profile is completely reversed by diets rich in Omega 3 PUFA, as is the vulnerability to ventricular fibrillation. Accumulating epidemiological evidence indicates that dietary PUFA (from fish) confer secondary protection from death due to cardiovascular events related to Alzheimers CV disease. In these studies, it was noted that those individuals who consumed diets high in Omega 3 PUFA also had a reduction in resting heart rate. Numerous other recent epidemiological studies have demonstrated a beneficial effect to a lower (but normal) heart rate with respect to morbid outcomes with CV disease. The Pharma industry has begun to capitalize upon these discoveries by initiating clinical outcome studies to reduce heart rate using bradycardic drug as the active arm. Results to date demonstrate that there is a moderate, but significant reduction in baseline and intrinsic (elimination of sympathetic and residual nerve control) heart rate following a 40-60 day diet of Omega 3 PUFA compared to a diet of Omega 6 PUFA. Analysis of data is ongoing for studies employed to identify mechanistic causes for altered beating rates in isolated sinoatrial nodal cells between the two dietary groups: 1) patch clamp protocols to evaluate their beating rate and also possible changes in some other electrophysiological parameters, 2) skinned cell methodologies to compare local calcium release (LCR) and sarcoplasmic reticulum (SR) load, and 3) cytosolic Ca2+ transients. The large amount of cardiac tissue collected is being analyzed for fatty acid content and incorporation. Gas chromatography of fatty acid methyl ester extracted from the ventricle, sinoatrial node, atria and aorta revealed overall increases in membrane n-3 PUFA in fish oil diet versus control diet. Mole to mole (Omega-3/Omega-6) ratios of the two most biologically active Omega-3 PUFAs DHA and EPA were found in ranges of all fish oil tissues from 3:1 to 31:1. Specifically, the affinity for n-3 EPA was found to be the highest in the sinoatrial node at 31:1 followed by the atria 29:1, aorta 27:1 and ventricle 3:1. The aorta showed the highest affinity for DHA at 21:1 followed by the ventricle 13:1, atria 15:1 and the sinoatrial node 8:1. Total Omega-3 fatty acids comprised 15% of total lipids in fish oil diets 2% in control diets. Also, there was an increase in incorporation of Omega-3 PUFA proportionate to the number of days on the fish oil diet. These data indicate an important cardiovascular tissue specific incorporation of dietary PUFA . To further elucidate signaling membrane changes, rabbit tissues were pooled (n=5) then fractionated through ultracentrifugation to isolate lipid rafts. These fractions were then extracted for protein or lipid analysis. Preliminary lipid analysis indicates that the PUFA diet significantly shifts lipid raft components (i.e. sphingomyelins, ceramides, gangliosides, and cholesterol, cardiolipin) that normally increase with age and/or a high fat (Omega-6) diet. These changes were also accompanied by decreases in lipid peroxidation markers 4-hydroxynonenal, 8-epi-prostaglanin F2 and significant changes in protein distribution between caveolin enriched microdomains. Proteins affected were from broad categories including channels, enzyme, SR localized proteins and mitochondrial proteins. Notably, Connexin 43, a critical component of the Gap junctional complex was present in membrane microdomains from control animals, but absent from PUFA treated animals (38 vs. 0 spectra). Membrane raft associated CX43 has been associated with non-functional CX43, and is increased in heart failure. All of these effects seem to reverse the normal age-related changes seen in these lipid profiles, and helps explain many of the beneficial effects of a high PUFA diet.

我们和其他人已经证明，长链多不饱和脂肪酸（PUFA）的饮食含量会影响其掺入细胞膜脂质筏中。 PUFAS效应的机制包括生物活性介质的释放，离子通道活性和细胞膜行为的变化。 PUFA对细胞离子稳态和氧化还原化学的影响产生巨大影响。 Omega 3 PUFA，种类繁多的PUFA，类型为docosohexanoic Acid的类型，免受致命后缺血性心律失常的保护，而Omega 6（不良的PUFA）促进了心律失常。随着啮齿动物年龄的增长，膜欧米茄3减少，欧米茄6增加。老鼠极易容易出现缺血性心室纤颤。富含Omega 3 PUFA的饮食，膜PUFA谱的年龄相关的变化以及对心室纤颤的脆弱性也完全逆转。 累积的流行病学证据表明，饮食中的PUFA（来自鱼类）赋予与阿尔茨海默氏症CV病有关的心血管事件引起的次要保护，以免死亡。在这些研究中，有人指出，那些在Omega 3 Pufa中食用饮食习惯的人的静息心率也降低了。关于CV疾病的病态结果，许多其他最近的流行病学研究表明，对较低（但正常）的心率具有有益作用。制药行业已开始通过启动临床结果研究来利用这些发现，以减少心跳药作为活跃部门的心率。 迄今为止的结果表明，与Omega 6 PUFA的饮食相比，在40-60天饮食的40-60天饮食之后，基线和内在（消除交感神经控制和残留神经控制）的心率显着降低。 为了确定两个饮食组之间孤立的弦乐节点细胞中的殴打率改变的机械原因的研究的数据分析正在进行中：1）斑块夹夹协议，以评估其跳动率，并在其他一些电生理学参数中可能发生变化，2）皮肤细胞方法，以比较局部钙化局部和sarcopopoplamic capoplamic capoplamic capoplimic capoplimic capoplimic capocumic capoplimic sr sr sr sr sr，瞬态。正在分析收集的大量心脏组织中的脂肪酸含量和掺入。 从心室，心房和主动脉提取的脂肪酸甲基酯的气相色谱显示，在鱼油饮食与对照饮食中，膜N-3 PUFA的总体增加。在所有鱼油组织的范围内发现了两个最具生物活性的omega-3 pufas dha和EPA的摩尔与摩尔（Omega-3/Omega-6）比。具体而言，发现对N-3 EPA的亲和力在31：1中是Sinoatrial节点中最高的，其次是Atria 29：1，Aorta 27：1和心室3：1。主动脉在21：1时显示出对DHA的最高亲和力，其次是心室13：1，Atria 15：1和Sinoatrial节点8：1。 omega-3脂肪酸总脂肪占鱼油饮食中脂质总脂质的15％，其中2％的对照饮食。同样，欧米茄3 PUFA的掺入与鱼油饮食的天数成正比也有所增加。这些数据表明饮食中的重要心血管组织特异性掺入。 为了进一步阐明信号传导膜的变化，合并兔组织（n = 5），然后通过超速离心分离以分离脂质筏。然后提取这些部分进行蛋白质或脂质分析。初步脂质分析表明，PUFA饮食会显着转移脂质筏成分（即鞘磷脂，神经酰胺，神经脂剂和胆固醇，心脂蛋白），通常会随着年龄和/或高脂肪（omega-6）而增加。这些变化还伴随着脂质过氧化标志物的降低4-羟基烯烯，8- pepi-prostaglanin f2，以及富集的小域中蛋白质分布的显着变化。受影响的蛋白质来自广泛类别，包括通道，酶，SR局部蛋白质和线粒体蛋白。值得注意的是，连接蛋白43是对照动物的膜微域中存在间隙连接复合物的关键成分，但没有PUFA治疗的动物（38 vs. 0光谱）。膜筏相关的CX43与非功能CX43有关，心力衰竭增加。所有这些影响似乎扭转了这些脂质谱中与年龄相关的正常变化，并有助于解释高PUFA饮食的许多有益作用。