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: 6098815
• 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: 1999-03-20 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098815
• 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.

老龄动物心脏更易发生缺血性损伤。 从衰老大鼠中分离的线粒体在复合物III中具有缺陷， 电子传递链此外，复合体III也是主要的网站 缺血后年轻和老年大鼠线粒体的缺陷。 最近，我们观察到细胞可渗透的神经酰胺也抑制 从大鼠肝脏、心脏和肌肉中分离的线粒体在复合物III处 电子传递链的位置。多项研究表明， 神经酰胺相关的脂质在老化的细胞或动物中升高。在 此外，肿瘤坏死因子α（TNF），增加细胞神经酰胺 通过激活鞘磷脂酶，浓度升高，缺血性 组织和衰老的动物。除了衰老和缺血， 以脂肪酸代谢异常为特征的其他代谢状况 也与TNF表达升高有关。此外，已知 心脏对脂肪酸的利用增加会加重 缺血再灌注后的心脏。似乎有一个因果关系 脂肪酸代谢异常与脑卒中发病的关系 可能通过异常细胞因子表达介导的组织损伤 和鞘脂信号转导。 有待检验的假设是，组织神经酰胺和TNF 内容，这导致一个压抑的线粒体复合物III，在老化和 心肌缺血导致衰老的易感性增加 心脏缺血性损伤。络合物III是氧的主要位点之一 自由基的产生。复合物III的抑制增加了 产生自由基，导致组织受损和抑郁 心脏功能在本提案中，我们将描述心脏细胞因子的特征 表达和脂质代谢与衰老异常的关系 使用分离的缓冲液灌注的Fischer的心脏线粒体和功能 344只大鼠心脏作为模型。将对6、18、24和28月龄的大鼠进行 研究了此外，衰老心脏的异常可以通过以下方式复制： 升高灌注介质中的脂肪酸含量和通过抑制脂肪酸 年轻大鼠的酸氧化。旨在预防脂肪酸的干预措施 流入心脏组织，TNF的积累，以及 神经酰胺应该保护衰老的心脏免受过度缺血的影响， 再灌注损伤这些干预措施可能包括肉毒碱 棕榈酰转移酶-I抑制剂、抗TNF抗体和抑制剂 其阻断由鞘磷脂水解产生神经酰胺， 鞘氨醇酰化