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Impaired ALDH2 activity decreases the mitochondrial respiration in H9C2 cardiomyocytes

机译:ALDH2活性受损会降低H9C2心肌细胞的线粒体呼吸

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Reactive oxygen species (ROS)-mediated reactive aldehydes induce cellular stress. In cardiovascular diseases such as ischemia-reperfusion injury, lipid-peroxidation derived reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) are known to contribute to the pathogenesis. 4HNE is involved in ROS formation, abnormal calcium handling and more importantly defective mitochondrial respiration. Aldehyde dehydrogenase (ALDH) superfamily contains NAD(P)+-dependent isozymes which can detoxify endogenous and exogenous aldehydes into nontoxic carboxylic acids. Therefore we hypothesize that 4HNE afflicts mitochondrial respiration and leads to cell death by impairing ALDH2 activity in cultured H9C2 cardiomyocyte cell lines. H9C2 cardiomyocytes were treated with 25, 50 and 7511M 4HNE and its vehicle, ethanol as well as 25, 50 and 75 pM disulfiram (DSF), an inhibitor of ALDH2 and its vehicle (DMSO) for 4 h. 4HNE significantly decreased ALDH2 activity, ALDH2 protein levels, mitochondrial respiration and mitochondrial respiratory reserve capacity, and increased 4HNE adduct formation and cell death in cultured H9C2 cardiomyocytes. ALDH2 inhibition by DSF and ALDH2 siRNA attenuated ALDH2 activity besides reducing ALDH2 levels, mitochondrial respiration and mitochondrial respiratory reserve capacity and increased cell death. Our results indicate that ALDH2 impairment can lead to poor mitochondrial respiration and increased cell death in cultured H9C2 cardiomyocytes. 2015 Elsevier Inc All rights reserved.
机译:活性氧(ROS)介导的活性醛诱导细胞应激。在诸如缺血-再灌注损伤的心血管疾病中,脂质过氧化衍生的反应性醛(例如4-羟基-2-壬烯醛(4HNE))是导致发病的原因。 4HNE与ROS的形成,钙的异常处理以及更重要的线粒体呼吸缺陷有关。醛脱氢酶(ALDH)超家族包含NAD(P)+依赖性同功酶,可以将内源性和外源性醛解毒成无毒的羧酸。因此,我们假设4HNE会影响线粒体呼吸并通过损害培养的H9C2心肌细胞系中的ALDH2活性而导致细胞死亡。将H9C2心肌细胞分别用25、50和7511M 4HNE及其媒介物,乙醇以及25、50和75 pM双硫仑(DSF),ALDH2抑制剂及其媒介物(DMSO)处理4小时。 4HNE显着降低了培养的H9C2心肌细胞的ALDH2活性,ALDH2蛋白水平,线粒体呼吸和线粒体呼吸储备能力,并增加了4HNE加合物的形成和细胞死亡。 DSF和ALDH2 siRNA对ALDH2的抑制作用除了降低ALDH2水平,线粒体呼吸作用和线粒体呼吸储备能力并增加细胞死亡外,还降低了ALDH2活性。我们的结果表明,ALDH2损伤可导致培养的H9C2心肌细胞线粒体呼吸不良并增加细胞死亡。 2015 Elsevier Inc保留所有权利。

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