FATTY ACID METABOLISM IN CARDIAC ISCHEMIA

拟议研究的长期目标是确定 这些因子在控制亚细胞和 长链脂肪酸（FA）在正常人和 缺血性心脏 与生理观察结果一致， 可逆性损伤、复氧 心肌是细胞脂质的积累，如所示 通过切除组织的电子显微镜检查， 核磁共振和正电子发射断层扫描。 因此，减少的FA氧化发生在 结构正常，并且氧化葡萄糖作为优选的燃料。 这些细胞中FA酯的积累可能在以下方面发挥作用： 收缩功能障碍和电生理变化， 膜扰动效应 在第一个具体目标中， FA酯与离体心脏膜的相互作用，以及 它们对特定膜位点的亲和力将与 是否存在心脏脂肪酸结合蛋白。 还有， FA酯的蛋白质识别位点减少的影响 在心脏膜上（例如，线粒体肉毒碱 移位酶，CAT）对FA酯停留时间的影响将是 研究了 负责变化的机制 这些识别位点的数量将在第二次研究 具体目标。 线粒体基质谷胱甘肽和 膜蛋白巯基在缺血中将与 FA中涉及的巯基依赖性过程的变化 新陈代谢. 具体而言，包括（1）潜在利率 当过量时，CAT限制酰基肉毒碱转运 运输部位因缺血/再灌注而失活（2） CAT与肉毒碱棕榈酰CoA转移酶（CPT）的偶联 其将酰基单元汇集到B-氧化（3）CoA-SH氧化（4） CPT动力学和对丙二酰辅酶A和（5）膜的敏感性 通过溶血磷脂酰基转移酶的脂质变化。 结果 这些实验将提供必要的信息来解释 超微结构，收缩和非侵入性观察 可逆性脑缺血损伤时脂质代谢异常 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.