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，饮食中长链多不饱和脂肪酸（PUFA）的含量会影响它们在细胞膜脂筏中的掺入。PUFAs作用的机制包括改变生物活性介质的释放、离子通道活性和细胞膜行为。多聚脂肪酸对细胞离子稳态和氧化还原化学有显著影响。Omega - 3 PUFA是一种好的PUFA，以二十二硫己酸为代表，可以预防致命的缺血性心律失常，而Omega - 6 PUFA是一种坏的PUFA，可以促进这些心律失常。随着啮齿类动物年龄的增长，细胞膜Omega - 3减少，Omega - 6增加。老年大鼠极易发生缺血性心室颤动。富含Omega - 3 PUFA的饮食完全逆转了与年龄相关的膜PUFA谱变化，也逆转了心室颤动的易感性。