Polyamine metabolism in heart and kidney ischemic injury

心肾缺血损伤中的多胺代谢

• 批准号: 6842212
• 负责人: MANOOCHER SOLEIMANI
• 金额: $ 15.35万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-06 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6842212
• 关键词: acyltransferase; biomarker; cytoprotection; cytotoxicity; enzyme activity; enzyme induction /repression; hydrogen peroxide; laboratory mouse; metabolism; myocardial ischemia /hypoxia; polyamines; renal ischemia /hypoxia; reperfusion

DESCRIPTION (provided by applicant): Conditions associated with ischemia/reperfusion injury (IRI) such as myocardial infarction and acute ischemic renal failure are among the major causes of morbidity and mortality. The pathophysiology of IRI is strikingly similar in heart and kidney, with enhanced production of toxic metabolites (i.e. H202), increased apoptosis, and cell death following reperfusion, raising the possibility that identical pathway(s) may mediate cell injury and dysfunction in both organs in IRI. In an attempt to identify the factors involved in the pathophysiology of IRI, suppression subtractive hybridization on RNA from normal rat kidneys and kidneys of animals subjected to 30 min of ischemia (renal artery ligation) followed by 12 hrs of reperfusion was performed. The results identified enhanced expression of Spermidine/Spermine N-1 acetyltransferase (SSAT), the rate limiting enzyme involved in the catabolism of polyamines, in IRI. Interestingly, thirty (30) min of ischemia (left anterior descending artery ligation) followed by 6-12 hrs of reperfusion resulted in the induction of SSAT in the injury zone in myocardium, with SSAT expression being almost undetectable in normal myocardium and increasing by >50-fold at 6 hrs of reperfusion. Enhanced SSAT expression in kidney and heart in IRI was associated with increased concentrations of putrescine, a mediator of apoptosis and a phenomenon indicative of increased activity of SSAT. Conditional overexpression of SSAT in cultured cells resulted in decreased cell growth. The studies outlined in this proposal will test the hypothesis that SSAT is a biomarker of cell injury and its increased expression reflects the extent of tissue damage associated with IRI in heart and kidney. We further hypothesize that enhanced expression of SSA T in kidney or heart leads to cell damage through depletion of polyamines, production of toxic metabolites (e.g. H202, putrescine and various aldehydes) and induction of apoptosis. To test these hypotheses, we propose to: 1. Examine the expression and regulation of SSAT and polyamine pathway in renal and heart IRI, 2. Ascertain the role of SSAT over expression on cell survival and susceptibility to injury in renal and cardiac IRI, and 3. Ascertain the mechanism of SSAT-mediated cell injury in renal and cardiac IRI. Insight into the expression and regulation of SSAT and other enzymes involved in polyamine metabolism in IRI will shed new lights into the pathophysiology of IRI in heart and kidney and may provide basis for novel diagnostic tests and therapeutic options targeted at early detection, prevention or treatment of ischemic heart attack and acute ischemic renal failure.

描述（由申请人提供）：与缺血/再灌注损伤（IRI）相关的病症，例如心肌梗塞和急性缺血性肾衰竭，是发病和死亡的主要原因。 IRI 的病理生理学在心脏和肾脏中惊人地相似，有毒代谢物（即 H2O2）的产生增加，细胞凋亡增加，再灌注后细胞死亡，增加了相同途径可能介导两个器官中细胞损伤和功能障碍的可能性在IRI。为了确定 IRI 病理生理学中涉及的因素，对正常大鼠肾脏和缺血 30 分钟（肾动脉结扎）然后再灌注 12 小时的动物肾脏的 RNA 进行了抑制消减杂交。结果发现，IRI 中亚精胺/精胺 N-1 乙酰转移酶 (SSAT) 的表达增强，SSAT 是参与多胺分解代谢的限速酶。有趣的是，三十（30）分钟的缺血（左前降支动脉结扎）随后6-12小时的再灌注导致在心肌损伤区诱导SSAT表达，而在正常心肌中SSAT表达几乎检测不到并且增加>再灌注 6 小时时增加 50 倍。 IRI 中肾脏和心脏中 SSAT 表达增强与腐胺浓度增加相关，腐胺是细胞凋亡的介质，也是 SSAT 活性增加的现象。在培养细胞中条件性过度表达 SSAT 会导致细胞生长下降。 该提案中概述的研究将检验以下假设：SSAT 是细胞损伤的生物标志物，其表达增加反映了心脏和肾脏中与 IRI 相关的组织损伤程度。我们进一步假设肾脏或心脏中 SSA T 表达的增强通过消耗多胺、产生有毒代谢物（例如 H2O2、腐胺和各种醛）和诱导细胞凋亡而导致细胞损伤。为了检验这些假设，我们建议： 1. 检查肾和心脏 IRI 中 SSAT 和多胺途径的表达和调节， 2. 确定 SSAT 过度表达对肾和心脏 IRI 中细胞存活和损伤易感性的作用，以及3. 确定SSAT介导的肾脏和心脏IRI细胞损伤的机制。对 IRI 中 SSAT 和其他参与多胺代谢的酶的表达和调节的深入了解将为心脏和肾脏中 IRI 的病理生理学提供新的线索，并可能为针对早期检测、预防或治疗 IRI 的新型诊断测试和治疗方案提供基础。缺血性心脏病和急性缺血性肾衰竭。