DIETARY FATTY ACID MODULATION OF MYOCARDIAL FUNCTION AND INFLUENCES ON AGING

这项研究计划始于1993年，目的是确定： 心肌膜磷脂脂肪酸的组成可以 通过改变饮食脂肪摄入量的类型而改变的；确定 如果这改变了衰老中的心脏功能，并辨别出 潜在的分子机制。以前已经表明，在 对老鼠的研究表明，对心律失常刺激的易感性增加 随着年龄和鱼油饮食富含omega-3多不饱和脂肪酸(FO)，取消了这一点 而富含饱和脂肪(SAT)的饮食会加剧 心律失常。在分离的工作大鼠心脏中，心肌O2 特别是在缺血后，SAT心脏的消耗量明显较高 但在O2-能量利用率高的FO心脏中显著减少 效率。这不是由于基础氧气消耗的任何变化，而是 相反，间接发现与细胞内钙离子变化有关 动态平衡，就像心脏灌入钌红，以阻止 线粒体(Mito)钙离子进入，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 随着年龄的增加(6个月比24个月)，模型的omega-6多不饱和脂肪酸含量增加 但显著降低了omega-3多不饱和脂肪酸的含量。SAT饮食加强了这一影响 而这些脂肪酸并没有随着年龄的增长而发生重大变化 与FO。我们还观察到，在分离的心肌细胞中，FO赋予 抵抗与年龄相关的钙耐量增加和 心律失常的发生，而SAT加剧了这些与年龄相关的影响。在……里面 分离的平滑肌细胞，SAT饮食增加和FO减少 细胞内一过性钙离子浓度随年龄增长而升高。最近，有研究表明 在Mito水平上定义氧气的低效利用，以及 测试这是否与SAT中Mito增加的Ca++循环有关 与FO相比，红心。呼吸控制率，这是一项衡量 耦合程度和热力学效率，Mito从 为红心而战。依赖钙离子激活的亚甲基丙酮酸脱氢酶和 24个月大鼠的[Ca++]Mito显著高于6个月大鼠和 这一效应在SAT组和FO组中得到了增强。得出的结论是 随着年龄的增长或SAT饮食导致的膜流动性降低 随着热力学降低，Mito H+和Ca++循环增加 效率。细胞和细胞内的物理化学状态 经老化和饮食脂质修饰的膜，调节一系列 细胞内效应器改变细胞器间的通讯和 随后，他们在心血管病理的病因学上做出反应。 因此，增加磷脂中omega-3多不饱和脂肪酸含量的影响可能 对心脏机械和代谢有重要的有益影响 随着年龄的增长而发挥作用。

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.