DIETARY FATTY ACID MODULATION OF MYOCARDIAL FUNCTION AND INFLUENCES ON AGING

膳食脂肪酸对心肌功能的调节及其对衰老的影响

• 批准号: 5200351
• 负责人: S PEPE
• 金额: --
• 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/5200351
• 关键词: action potentials; aging; animal old age; arrhythmia; calcium channel blockers; calcium flux; dietary lipid; enzyme activity; heart cell; heart function; homeostasis; hypoxia; immature animal; laboratory rat; membrane activity; membrane lipids; myocardium; nutrition of aging; nutrition related tag; omega 3 fatty acid; oxygen consumption; smooth muscle; thermodynamics; unsaturated fatty acids; vasodilation

This research program was commenced in 1993 to identify: whether the composition of myocardial membrane phospholipid fatty acids can be altered by modification of the type of dietary fat intake; to ascertain if this alters cardiac function in aging and discern the nature of the underlying molecular mechanisms. It has been shown previously that in studies with rats that the vulnerability to arrhythmic stimuli increased with age and fish oil diet rich in omega-3 PUFAs (FO) abolished this effect whereas a diet rich in saturated fat (SAT) exacerbated arrhythmogenesis. In isolated working rat hearts, myocardial O2 consumption, especially after ischemia, was distinctly high in SAT hearts but markedly reduced in FO hearts that had high O2- energy utilization efficiency. This was not due to any change in basal O2 consumption but rather was indirectly found to be related to altered intracellular Ca++ homeostasis as when hearts were perfused with ruthenium red, to block mitochondrial (MITO) Ca++ entry,the thermodynamic efficiency increased in SAT hearts. We observed that myocardial membranes in this dietary model, with increased age (6 vs 24mo), had increased omega-6 PUFA content but markedly reduced omega-3 PUFA content. SAT diet augmented this effect whereas no major change in these fatty acids with increased age occurred with FO. We also observed that in isolated cardiac myocytes, FO confers resistance against an age-linked increase in Ca++-intolerance and arrhythmogenesis, whilst SAT exacerbates these age-linked effects. In isolated smooth muscle cells, SAT diet augments and FO attenuates age-related increases in cytosolic Ca++ transient. Recently, studies were conducted to define the less efficient use of O2 at the MITO level and test whether this was related to increased Ca++ cycling by MITO in SAT hearts compared to FO. The respiratory control ratio, an index of the degree of coupling and thermodynamic efficiency, was raised in MITO from FO hearts. Ca++-dependent activation of MITO pyruvate dehydrogenase and [Ca++]MITO was significantly greater in preps from 24mo rats vs 6mo and this effect was augmented in SAT groups vs FO. It is concluded that decreased membrane fluidity with aging or SAT diet contributes to increased MITO H+ and Ca++ cycling with decreased thermodynamic efficiency. The physicochemical state of cell and intracellular membranes, modified by aging and dietary lipids, regulates a range of intracellular effectors which alter inter-organelle communication and subsequently their response in the etiology of cardiovascular pathology. The effect of increased omega-3 PUFA content of phospholipids may thus have important beneficial consequences on cardiac mechanical & metabolic function with aging.

这项研究计划于1993年开始，以确定： 心肌膜磷脂脂肪酸的组成， 通过改变膳食脂肪摄入类型而改变;确定 如果这改变了衰老中的心脏功能， 潜在的分子机制。以前已经证明，在 对老鼠的研究表明， 随着年龄的增长和富含omega-3多不饱和脂肪酸（FO）的鱼油饮食废除了这一点， 而富含饱和脂肪（SAT）的饮食会加剧 胚胎发生在离体工作大鼠心脏中， 在SAT心脏中，尤其是在缺血后， 但在具有高O2能量利用的FO心脏中显著降低 效率这不是由于基础O2消耗量的任何变化， 相反，间接发现与细胞内Ca++改变有关 当心脏被钌红灌注时， 线粒体（MITO）Ca++内流，热力学效率增加 在SAT心中。我们观察到这种饮食中的心肌膜 模型，随着年龄的增加（6 vs 24个月），omega-6 PUFA含量增加 但显著降低了ω-3多不饱和脂肪酸含量。SAT饮食增强了这种效果 而随着年龄的增长，这些脂肪酸没有发生重大变化 关于FO我们还观察到，在离体心肌细胞中，FO赋予 抵抗与年龄相关的Ca++不耐受增加， 而SAT加剧了这些与年龄相关的影响。在 分离的平滑肌细胞，SAT饮食增强和FO减弱 与年龄相关的胞质Ca++瞬时增加。最近，研究 进行，以确定在MITO水平上O2的使用效率较低， 测试这是否与SAT中MITO增加的Ca++循环有关 心与心相比。呼吸控制率，一个指标， 耦合度和热力学效率，在MITO中从 FO心脏。MITO丙酮酸脱氢酶的Ca++依赖性活化和 [Ca++]MITO在24个月大鼠的制备中显著高于6个月大鼠， 与FO组相比，SAT组的这一效应增强。它的结论是 衰老或SAT饮食导致膜流动性降低， 增加MITO H+和Ca++循环，降低热力学 效率细胞和细胞内的物理化学状态 膜，由老化和饮食脂质修改，调节一系列的 改变细胞器间通讯的细胞内效应物， 随后他们的反应，心血管病理学的病因。 因此，磷脂中omega-3 PUFA含量增加的作用可能 对心脏机械和代谢有重要的有益影响 功能老化。