FATTY ACID METABOLISM IN CARDIAC ISCHEMIA

心肌缺血时的脂肪酸代谢

• 批准号: 2219082
• 负责人: Jeanie B. MC MILLIN
• 金额: $ 17.8万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-15 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2219082
• 关键词: acetyl coA carboxylase; bioenergetics; dogs; fatty acid metabolism; heart contraction; heart metabolism; isomer; laboratory rat; lipid metabolism; mitochondria; myocardial ischemia /hypoxia; oxidation; sarcoplasmic reticulum; tissue /cell culture; transferase

This proposal will study the cellular regulation of fatty acid oxidation (FAO) in ischemic hearts and cultured neonatal rat cardiac myocytes. The role of the cardiac isoform of acetyl-CoA carboxylase (C-ACC) in the cytoplasmic synthesis of malonyl-CoA and the subsequent inhibition of carnitine palmitoyltransferase I (CPT-I) in unknown. Lactate may affect the expression of C-ACC to regulate FAO during ischemia and early reperfusion, conditions in which tissue lactate is elevated. Transient activation of C-ACC by te production of lactate during ischemia may shift oxidative metabolism to the use of carbohydrate when these conditions prevail during early reperfusion. Recovery of fatty acid as an energy fuel should parallel a reduction in C-ACC activity. How C-ACC activity is regulated by phosphorylation will be correlated with tissue levels of lactate and CAMP, and with its enzyme product, malonyl-CoA. How malonyl-CoA modulates CPT-I activity will be investigated by examining the kinetics of substrate and inhibitor interaction and CPT-I sensitivity to malonyl-CoA in control and hypoxic cardiac myocytes in culture. A malonyl-CoA-sensitive isoform of CPT located in the sarcoplasmic reticulum (SR) will be isolated, cloned and expressed in yeast. Intact tissue, cultured cardiac cells, and isolated organelles will be analyzed immunologically and biochemically to examine cardiac metabolism in control and ischemic injured tissue. The presence and location of different isoforms of CPT-I also will be determined using the same techniques together with cell biology and immunoelectron microscopy. These experiments are important for defining the subcellular mechanisms that regulate FAO in the normal heart. No information is available suggesting that C-ACC plays a role in the regulation of FAO by malonyl- CoA in the heart, nor are there any data for cardiac muscles as for liver that describe a role for an adaptive response of CPT-I to physiological and pathological stimuli. Determining the changes in these regulatory mechanisms in the metabolic and functional responses of the ischemic, reperfused heart will provide information relevant to the therapeutic management of the stunned myocardium, and about the energetics of recovery following ischemia.

这项计划将研究脂肪酸氧化的细胞调节。 (FAO)在缺血心脏和培养的新生大鼠心肌细胞中。这个 心脏乙酰辅酶A羧基酶亚型(C-ACC)在心肌梗死中的作用 丙二酰辅酶A的细胞质合成及其随后的抑制作用 肉毒碱棕榈酰转移酶I(CPT-I)未知。乳酸盐可能会影响 C-ACC在脑缺血及早期表达对FAO的调节作用 再灌流，组织乳酸升高的状态。瞬变 缺血时乳酸生成对C-ACC的激活可能 将氧化代谢转变为使用碳水化合物时， 在再灌流早期条件占优势。脂肪酸的回收利用 一种能源燃料应该与C-ACC活性的减少同时进行。C-Access如何 活性受磷酸化调节将与组织相关 乳酸和cAMP水平及其酶产物丙二酰辅酶A。 丙二酰辅酶A如何调节CPT-I活性将由 底物与缓蚀剂相互作用及CPT-I的动力学研究 对照和低氧心肌细胞对丙二酰辅酶A的敏感性 文化。丙二酰辅酶A敏感的CPT异构体位于 肌浆网(SR)的分离、克隆和表达 酵母。完整的组织、培养的心肌细胞和分离的细胞器 将进行免疫学和生化分析，以检查心脏 对照和缺血损伤组织中的代谢。在场和 不同的CPT-I亚型的位置也将使用 同样的技术结合了细胞生物学和免疫电子学 显微镜。 这些实验对于确定亚细胞机制很重要。 在正常的心脏里管理粮农组织。没有可用的信息 提示C-ACC在丙二酸基-1，4-丙二醛对粮农组织的调节中起作用。 心脏中的CoA，也没有任何关于心肌的数据 肝脏对CPT-I的适应性反应的作用 生理和病理刺激。确定这些方面的变化 血管紧张素转换酶代谢和功能反应的调节机制 缺血、再灌流的心脏将提供与 顿抑心肌的治疗，以及关于 脑缺血后恢复的能量学。