FATTY ACID METABOLISM IN CARDIAC ISCHEMIA

拟议研究的长期目标是确定 对亚细胞和细胞外基质起控制作用的因素 长链脂肪酸(FA)在人体内的代谢去向 缺血型心脏。与生理观察相一致的 可逆性损伤、复氧后收缩功能受抑 如图所示，心肌是细胞内脂质的积聚。 通过切除组织的电子显微镜，并无创地通过 核磁共振和正电子发射断层扫描。 因此，在符合以下条件的细胞中FA氧化减少 结构正常，氧化葡萄糖作为首选燃料。 这些细胞中FA酯的积累可能会在 收缩功能障碍和电生理改变 膜扰动效应。在第一个具体目标中， FA酯与离体心肌膜的相互作用 它们对特定膜部位的亲和力将与 存在或不存在心脏脂肪酸结合蛋白。另外， 蛋白质识别位点减少对脂肪酸酯类的影响 在心肌膜上(例如，线粒体肉毒碱、酰卡尼汀 转位酶，CAT)在FA酯上的停留时间将为 调查过了。负责改革的机制 这些识别地点的数量将在第二个月进行研究 明确目标。线粒体基质谷胱甘肽和谷胱甘肽 膜蛋白巯基在脑缺血中的作用 FA所涉及的巯基依赖过程的变化 新陈代谢。具体地说，这些因素包括(1)潜在利率 过量时猫对酰基肉碱转运的限制 运输部位因缺血/再灌流而失活(2) 肉碱棕榈酰辅酶A转移酶(CPT)与CAT的偶联 它将酰基单元漏斗为B-氧化(3)CoA-SH氧化(4) CPT动力学及其对丙二酰辅酶A和(5)膜的敏感性 脂类通过溶血磷脂酰基转移酶改变。结果来自 这些实验将提供必要的信息来解释 血管的超微结构、收缩和无创性观察 大鼠可逆性脑缺血损伤时脂代谢异常 心。

The long term objective of the proposed research is to define factors which play a role in control of the subcellular and metabolic fate of long chain fatty acids (FA) in the normal and ischemic heart. Coincident with physiological observations of depressed contractility in reversibly injured, reoxygenated myocardium is the accumulation of cellular lipid, as demonstrated by electron microscopy of excised tissue, and noninvasively by nuclear magnetic resonance and positron emission tomography. Therefore, decreased FA oxidation occurs in cells which are structurally normal, and which oxidize glucose as a preferred fuel. FA ester accumulation in these cells may then play a role in contractile dysfunction and electrophysiological changes via membrane perturbant effects. In the first specific aim, interaction of FA esters with isolated cardiac membranes, and their affinity for specific membrane sites will be related to the presence or absence of cardiac fatty acid binding protein. Also, the influence of decreased protein recognition sites for FA esters on cardiac membranes (e.g., mitochondrial carnitine acylcarnitine translocase, CAT) on FA ester residence times will be investigated. The mechanisms responsible for changes in the numbers of these recognition sites will be studied in the second specific aim. Alterations in mitochondrial matrix glutathione and membrane protein sulfhydryls in ischemia will be related to changes in sulfhydryl-dependent processes involved in FA metabolism. Specifically, these include (1) potential rate limitation of acylcarnitine transport by CAT when excess transport sites are inactivated by ischemia/reperfusion (2) coupling of CAT with carnitine palmitoyl CoA transferase (CPT) which funnels acyl units to B-oxidation (3) CoA-SH oxidation (4) CPT kinetics and sensitivity to malonyl-CoA and (5) membrane lipid changes via lysophospholipid acyl transferase. Results from these experiments will provide information necessary to explain ultrastructural, contractile and noninvasive observations of abnormal lipid metabolism during reversible ischemic injury in the heart.