A PUFA Dietary Intervention for Heart Rate

PUFA 饮食干预心率

• 批准号: 8335786
• 负责人: Edward Lakatta
• 金额: $ 25.83万
• 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/8335786
• 关键词: 4 hydroxynonenal; Acids; Affect; Affinity; Age; Alzheimer' s Disease; Aorta; Arrhythmia; Calcium; Cardiac; Cardiolipins; Cardiovascular system; Cells; Ceramides; Cessation of life; Chemistry; Cholesterol; Clinical; Data; Data Analyses; Diet; Dietary Intervention; Disease; Elderly; Epidemiologic Studies; Epidemiology; Esters; Event; Fatty Acid Desaturases; Fatty Acids; Fatty acid glycerol esters; Fish Oils; Fishes; Gangliosides; Gas Chromatography; Heart Atrium; Heart Rate; Homeostasis; Image; Individual; Industry; Ion Channel; Ions; Link; Lipid Peroxidation; Lipids; Membrane; Membrane Lipids; Membrane Microdomains; Methodology; Modeling; Mole the mammal; Nerve; Nodal; Nonesterified Fatty Acids; Omega-3 Fatty Acids; 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

We, and others, have demonstrated that dietary content of long chain polyunsaturated fatty acids (PUFA) affects their incorporation into cell membrane lipid rafts. 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 and 8-epi-prostaglanin F2. We also observed significant increases in the ratio of unsaturated free fatty acids (C16:1 and C24:1) which are indicative of PUFA inhibition of fatty acid desaturase. 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，饮食中长链多不饱和脂肪酸(PUFA)的含量会影响它们并入细胞膜脂筏。多不饱和脂肪酸对细胞离子动态平衡和氧化还原化学有显著影响。以二十二碳己酸为代表的多不饱和脂肪酸的优良品种欧米茄3多不饱和脂肪酸可以预防致命的缺血后心律失常，而多不饱和脂肪酸的劣质品种欧米茄6则促进这些心律失常的发生。随着啮齿动物年龄的增加，膜Omega 3减少，Omega 6增加。老年大鼠极易发生缺血后的室颤。富含欧米茄3多不饱和脂肪酸的饮食可以完全逆转与年龄相关的细胞膜PUFA谱的变化，就像对心室颤动的易感性一样。 越来越多的流行病学证据表明，饮食中的多不饱和脂肪酸(来自鱼类)可提供二级保护，防止因与阿尔茨海默氏病相关的心血管事件而死亡。在这些研究中，人们注意到那些摄入高欧米茄3多不饱和脂肪酸饮食的人的静息心率也有所降低。许多其他最近的流行病学研究表明，较低(但正常)的心率对心血管疾病的病态结果有好处。制药行业已经开始利用这些发现，启动临床结果研究，使用心动过缓药物作为主动臂来降低心率。 到目前为止的结果表明，与欧米茄6多不饱和脂肪酸相比，在40-60天的饮食中，欧米茄3多不饱和脂肪酸的基线心率和内在心率(消除交感神经和残余神经控制)有适度但显著的降低。 数据分析正在进行中，用于确定两个饮食组之间分离的窦房结细胞搏动频率改变的机制原因：1)膜片钳协议，以评估其搏动频率和其他一些电生理参数的可能变化，2)皮肤细胞方法，比较局部钙释放(LCR)和肌浆网(SR)负荷，以及3)胞浆钙瞬变。收集的大量心脏组织正在进行脂肪酸含量和掺入分析。 从脑室、窦房结、心房和主动脉中提取的脂肪酸甲酯的气相色谱分析表明，鱼油饲料中膜n-3多不饱和脂肪酸含量总体上高于对照饲料。最具生物活性的两种Omega-3多不饱和脂肪酸DHA和EPA的摩尔比(Omega-3/Omega-6)在3：1到31：1的鱼油组织中均有发现。其中，n-3EPA在窦房结的亲和力最高，为31：1，其次是心房29：1，主动脉27：1，脑室3：1。中耳15：1，窦房结8：1。鱼油饲料中总Omega-3脂肪酸占总脂肪的15%，对照组为2%。此外，欧米茄-3多不饱和脂肪酸的摄入量与鱼油饮食的天数成比例增加。这些数据表明饮食中多不饱和脂肪酸在心血管组织中具有重要的特异性。 为了进一步阐明信号膜的变化，将兔组织混合(n=5)，然后通过超速离心法分离脂筏。这些组分随后被提取用于蛋白质或脂肪分析。初步的脂质分析表明，多不饱和脂肪酸饮食显著改变了通常随年龄和/或高脂肪(欧米茄-6)饮食增加的脂筏成分(即神经鞘蛋白、神经酰胺、神经节苷脂和胆固醇、心磷脂)。这些变化还伴随着脂质过氧化标记物4-羟基壬烯醛和8-表前列腺素F2的减少。我们还观察到不饱和脂肪酸(C16：1和C24：1)的比例显著增加，这表明多不饱和脂肪酸抑制脂肪酸去饱和酶。所有这些影响似乎逆转了在这些血脂谱中看到的正常年龄相关的变化，并有助于解释高PUFA饮食的许多有益影响。