Downregulation of peroxisome proliferator-activated receptor-α gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity
Downregulation of peroxisome proliferator-activated receptor-α gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity
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DOI：
10.1161/circulationaha.105.536318
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发表时间：
2005-07-19
期刊：
影响因子：
37.8
通讯作者：
Taegtmeyer, H
中科院分区：
文献类型：
--
作者：
Dewald, O;Sharma, S;Taegtmeyer, H
背景-过氧化物酶体增殖物激活受体-α（PPAR-alpha），一种调节脂肪酸代谢的转录因子，调节心脏的底物偏好。虽然在急性缺血中，底物偏好从脂肪酸转换为葡萄糖，但反复缺血中的代谢基因表达没有得到很好的描述。在反复缺血/再灌注（I/R）诱导的缺血性心肌病小鼠模型中，我们假设过氧化物酶体增殖物激活受体α（PPAR α）的下调受活性氧调节，并且是维持心脏收缩功能所必需的。每天在C57/BL 6小鼠、过表达细胞外超氧化物歧化酶的小鼠和用PPAR α激动剂-WY-14，643处理的小鼠中进行（15分钟）。在重复I/R的3、5、7和28天以及停止I/R后的15和30天测量超声心动图、组织学和候选基因表达。重复I/R与PPAR α调节基因和两种肌球蛋白重链亚型转录水平的下调相关，这在I/R停止时是可逆的。过量表达EC-SOD可防止重复I/R引起的PPAR α调控基因和肌球蛋白同工酶基因的下调。此外，再激活的小鼠暴露于重复I/R恶化收缩功能，诱导微梗死，并增加心肌内甘油三酯沉积，提示心脏lipotoxic.Conclusions功能-代谢和肌球蛋白亚型基因表达在重复I/R是由活性氧介导的。此外，我们认为，在重复I/R中下调PPAR α是一种适应性机制，能够防止缺血心肌的脂毒性。
Background - The peroxisome proliferators - activated receptor-alpha (PPAR alpha), a transcription factor that modulates fatty acid metabolism, regulates substrate preference in the heart. Although in acute ischemia there is a switch in substrate preference from fatty acids to glucose, metabolic gene expression in repetitive ischemia is not well described. In a mouse model of ischemic cardiomyopathy induced by repetitive ischemia/reperfusion (I/R), we postulated that downregulation of PPAR alpha is regulated by reactive oxygen species and is necessary for maintaining contractile function in the heart.Methods and Results - Repetitive closed-chest I/R ( 15 minutes) was performed daily in C57/BL6 mice, mice overexpressing extracellular superoxide dismutase, and mice treated with the PPAR alpha agonist-WY-14,643. Echocardiography, histology, and candidate gene expression were measured at 3, 5, 7, and 28 days of repetitive I/R and 15 and 30 days after discontinuation of I/R. Repetitive I/R was associated with a downregulation of PPAR alpha-regulated genes and both myosin heavy chain isoform transcript levels, which was reversible on discontinuation of I/R. Overexpression of EC-SOD prevented the downregulation of PPAR alpha-regulated genes and myosin iso-genes by repetitive I/R. Furthermore, reactivation of PPAR alpha in mice exposed to repetitive I/R worsened contractile function, induced microinfarctions, and increased intramyocardial triglyceride deposition, features suggestive of cardiac lipotoxicity.Conclusions - Metabolic and myosin isoform gene expression in repetitive I/R is mediated by reactive oxygen species. Furthermore, we suggest that downregulation of PPAR alpha in repetitive I/R is an adaptive mechanism that is able to prevent lipotoxicity in the ischemic myocardium.