Decreased cardiac mitochondrial NADP+-isocitrate dehydrogenase activity and expression:: a marker of oxidative stress in hypertrophy development
Decreased cardiac mitochondrial NADP+-isocitrate dehydrogenase activity and expression:: a marker of oxidative stress in hypertrophy development
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DOI：
10.1152/ajpheart.00378.2004
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发表时间：
2004-11-01
影响因子：
4.8
通讯作者：
Des Rosiers, C
中科院分区：
文献类型：
--
作者：
Benderdour, M;Charron, G;Des Rosiers, C
氧化应激增加和能量代谢改变导致的线粒体功能障碍被认为在心肌肥厚的发展和进展到衰竭中发挥了作用，尽管事件的顺序仍有待阐明。本研究旨在研究肥厚发展对线粒体NADP(+)-异柠檬酸脱氢酶(mNADP(+)-ICDH)活性和表达的影响，该酶是控制氧化还原和能量状态的代谢酶。我们扩展了我们先前的发现，即在7周龄的自发性高血压大鼠(SHR)肥厚形成之前，通过脂质过氧化产物4-羟基壬烯醛(HNE)的翻译后修饰使其失活(Benderdour等人)。生物化学杂志278：45154 45159,2003年)。在这项研究中，我们使用了7周、15周和30周龄的SHR和Spraogue-Dawley(SD)大鼠进行腹主动脉缩窄。与年龄匹配的Wistar-京都(WKY)大鼠相比，SHR大鼠心脏mNADP(+)-ICDH活性显著降低25%，这在时间上先于其蛋白和mRNA表达水平的下降(10%~35%)和肥大标志物的增加。SHR中mNADP(+)-ICDH活性的慢性和持续性丧失与各年龄段组织中HNE-mNADP(+)-ICDH和总HNE-蛋白加合物的积累增加有关，并与参与抗氧化或能量代谢的其他线粒体酶的活性变化相对照。数据的双因素方差分析还显示，年龄对SHR和WKY心脏测量的大多数参数有显著影响。在缩窄的SD大鼠，mNADP(+)-ICDH的活性、蛋白和mRNA的表达降低了25%-35%，而用肾素-血管紧张素系统抑制剂治疗SHR或缩窄的SD大鼠后，mNADP(+)-ICDH的活性、蛋白和mRNA的表达均恢复正常，从而防止或减轻了肥厚。总之，我们的数据显示，心肌mNADP(+)-ICDH的活性和表达在肥厚发展过程中受到不同和顺序的影响，并且在较小程度上与年龄有关。心肌mNADP(+)-ICDH活性降低，至少部分归因于HNE加合物的形成，似乎是肥厚发展中线粒体氧化应激相关变化的一个相关的早期和持久的标志。潜在地，这也可能有助于心肌病的病因学。
Mitochondrial dysfunction subsequent to increased oxidative stress and alterations in energy metabolism is considered to play a role in the development of cardiac hypertrophy and its progression to failure, although the sequence of events remains to be elucidated. This study aimed at characterizing the impact of hypertrophy development on the activity and expression of mitochondrial NADP(+)-isocitrate dehydrogenase (mNADP(+)-ICDH), a metabolic enzyme that controls redox and energy status. We expanded on our previous finding of its inactivation through posttranslational modification by the lipid peroxidation product 4-hydroxynonenal (HNE) in 7-wk-old spontaneously hypertensive rat (SHR) hearts before hypertrophy development (Benderdour et al. J Biol Chem 278: 45154 45159, 2003). In this study, we used 7-, 15-, and 30-wk-old SHR and Sprague-Dawley (SD) rats with abdominal aortic coarctation. Compared with age-matched control Wistar-Kyoto (WKY) rats, SHR hearts showed a significant 25% decrease of mNADP(+)-ICDH activity, which preceded in time 1) the decline in its protein and mRNA expression levels ( between 10% and 35%) and 2) the increase in hypertrophy markers. The chronic and persistent loss of mNADP(+)-ICDH activity in SHR was associated with enhanced tissue accumulation of HNE-mNADP(+)-ICDH and total HNE-protein adducts at all ages and contrasted with the profile of changes in the activity of other mitochondrial enzymes involved in antioxidant or energy metabolism. Two-way ANOVA of the data also revealed a significant effect of age on most parameters measured in SHR and WKY hearts. The mNADP(+)-ICDH activity, protein, and mRNA expression were reduced between 25% and 35% in coarctated SD rats and were normalized by treatment of SHR or coarctated SD rats with renin-angiotensin system inhibitors, which prevented or attenuated hypertrophy. Altogether, our data show that cardiac mNADP(+)-ICDH activity and expression are differentially and sequentially affected in hypertrophy development and, to a lesser extent, with aging. Decreased cardiac mNADP(+)-ICDH activity, which is attributed at least in part to HNE adduct formation, appears to be a relevant early and persistent marker of mitochondrial oxidative stress-related alterations in hypertrophy development. Potentially, this could also contribute to the aetiology of cardiomyopathy.