ABNORMAL FATTY ACID METABOLISM AND CYTOKINES IN AGING HEARTS

衰老心脏中脂肪酸代谢和细胞因子的异常

• 批准号: 6218771
• 负责人: KOU-YI TSERNG
• 金额: $ 0.23万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6218771
• 关键词: acetyl coA acetyltransferase; aging; animal old age; animal tissue; biological signal transduction; ceramides; cytokine receptors; disease /disorder model; electron transport; enzyme activity; enzyme linked immunosorbent assay; fatty acid metabolism; free radical oxygen; gas chromatography mass spectrometry; juvenile animal; laboratory rat; mitochondria; myocardial ischemia /hypoxia; oxygen consumption; phospholipids; polymerase chain reaction; receptor expression; reperfusion; tumor necrosis factor alpha; western blottings

Heart from aging animal is more susceptible to ischemic injury. Mitochondria isolated from aging rats have defects in complex III of electron transport chain. In addition, complex III is also the main site of defect in mitochondria isolated from young and old rats after ischemia. Recently, we observed that cell-permeable ceramides also inhibit mitochondria isolated from rat liver, heart, and muscle at the complex III site of electron transport chain. A number of studies have shown that ceramide-related lipids are elevated in aging cells or animals. In addition, tumor necrosis factor alpha (TNF), which increase cell ceramide concentration by activating sphingomyelinase, is elevated in ischemic tissues and in aging animals. Besides aging and ischemia, a number of other metabolic conditions characterized by abnormal fatty acid metabolism are also associated with elevated TNF expression. Furthermore, it is known that increased utilization of fatty acids by hearts exaggerates the injury of hearts after ischemia-reperfusion. It appears that there is a causal relationship between abnormal fatty acid metabolism and the onset of tissue damage which might be mediated through abnormal cytokine expression and sphingolipid signal transduction. The hypothesis to be tested is that elevated tissue ceramide and TNF content, which lead to a depressed mitochondrial complex III, in aging and cardiac ischemia contribute to the increased susceptibility of aging hearts to ischemic injury. Complex III is one of the major sites of oxygen free radical production. A inhibition of complex III increased the production of free radical which leads to tissue damaged and depressed heart functions. In this proposal, we will characterize cardiac cytokine expression and lipid metabolism in relation to aging abnormality in cardiac mitochondria and function using isolated buffer perfused Fischer 344 rat hearts as model. Rats at 6, 18, 24, and 28 month age will be studied. Furthermore, the abnormality in aging hearts can be duplicated by elevated fatty acid content in perfusion medium and by inhibiting fatty acid oxidation in young rats. Interventions aimed at preventing fatty acid flux into cardiac tissue, the accumulation of TNF, and the production of ceramides should protect aging hearts from exaggerated ischemia- reperfusion injury. These interventions could include carnitine palmitoyltransferase-I inhibitors, anti-TNF antibodies, and inhibitors which block the production of ceramides from sphingomyelin hydrolysis of sphingosine acylation.

老龄动物的心脏更容易发生缺血性损伤。 衰老大鼠分离的线粒体存在复合体III缺陷 电子传输链。此外，复合体III也是主要的地点 从幼年和老年大鼠脑缺血后分离的线粒体缺陷。 最近，我们观察到细胞通透性神经酰胺也能抑制 从大鼠肝脏、心脏和肌肉中分离的线粒体复合体III 电子传输链的位置。许多研究表明， 神经酰胺相关的血脂在老化的细胞或动物中升高。在……里面 此外，肿瘤坏死因子α(TNF)可增加细胞神经酰胺 通过激活鞘磷脂酶而产生的浓度在缺血期升高 组织和衰老的动物体内。除了衰老和缺血，还有一些 其他以脂肪酸代谢异常为特征的代谢状况 也与肿瘤坏死因子的表达升高有关。此外，众所周知， 心脏对脂肪酸的利用增加会夸大伤害 对缺血再灌流后心脏的保护作用。这似乎是有原因的。 脂肪酸代谢异常与糖尿病发病的关系 可能通过细胞因子异常表达介导的组织损伤 和鞘脂信号转导。 需要检验的假设是组织神经酰胺和肿瘤坏死因子升高 内容物，导致线粒体复合体III被抑制，在衰老和 心肌缺血增加了衰老的易感性 心脏到缺血性损伤。络合物III是氧的主要位置之一 自由基的产生。抑制络合物III增加了 产生自由基，导致组织受损和抑制 心脏功能。在这项提案中，我们将描述心脏细胞因子 衰老异常与脑组织表达及脂代谢的关系 离体缓冲费休法心肌线粒体及其功能的研究 344只大鼠心脏作为模型。6、18、24和28个月龄的大鼠将被 学习。此外，老化心脏中的异常可以通过以下方式复制 提高灌流液中脂肪酸含量及抑制脂肪的作用 幼年大鼠的酸氧化。旨在预防脂肪酸的干预措施 进入心脏组织的流量，肿瘤坏死因子的积累，以及 神经酰胺应该保护老化的心脏免受夸大的缺血- 再灌注损伤。这些干预措施可能包括肉碱 棕榈酰转移酶-I抑制剂、抗肿瘤坏死因子抗体和抑制剂 阻止神经鞘磷脂的水解物产生神经酰胺 鞘氨醇酰化。