Effects of Aging on Cardiac Oxidative Stress and Transcriptional Changes in Pathways of Reactive Oxygen Species Generation and Clearance.
Effects of Aging on Cardiac Oxidative Stress and Transcriptional Changes in Pathways of Reactive Oxygen Species Generation and Clearance.
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DOI：
10.1161/jaha.120.019948
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发表时间：
2021-08-17
影响因子：
5.4
通讯作者：
Jahangir A
中科院分区：
文献类型：
--
作者：
Rizvi F;Preston CC;Emelyanova L;Yousufuddin M;Viqar M;Dakwar O;Ross GR;Faustino RS;Holmuhamedov EL;Jahangir A
年龄相关性心脏病是发病率和死亡率增加的重要因素。新出现的证据表明，心肌细胞内的线粒体有助于与年龄相关的活性氧（ROS）生成增加，这在衰老相关的心脏疾病中起着至关重要的作用。本研究调查了分离自成年（6个月）和老年（24个月）Fischer 344大鼠的心肌细胞以及心功能保留的成年（18-65岁）和老年（>65岁）患者的心脏组织中ROS产生的差异。超氧化物歧化酶可降解铁细胞色素c还原试验（1.32±0.63对0.76±0.31 nMol/mg/min; P=0.001）超氧化物和H2 O2产生，以二氯荧光素二乙酸酯荧光测定（1646±428对699±329，P=0.04），老年心肌细胞显著高于成年心肌细胞。通过MitoSOX荧光检测，在线粒体电子传递链复合物I相关的氧化应激增加中发现大鼠和人类之间年龄相关变化的相似性（53.66±18.58）对（22.81±12.60）; P=0.03）和4-HNE加合物水平（187.54±54.8 vs 47.83±16.7 ng/mg蛋白，P=0.0063），表明老年人的过氧化作用增加。这些差异与老年人和大鼠心脏中调节ROS稳态途径的基因功能富集的变化相关。功能合并的集体网络和途径富集分析揭示了人类和大鼠衰老相关网络中优先考虑的共同基因，这些基因在衰老的人类和大鼠心脏中富集了线粒体复合物I的功能术语和共同途径。衰老使心脏内ROS积聚的线粒体和线粒体外机制敏感。转录组的网络分析突出了与大鼠和人类心脏中常见的衰老相关ROS稳态途径相关的关键元件。
Age‐related heart diseases are significant contributors to increased morbidity and mortality. Emerging evidence indicates that mitochondria within cardiomyocytes contribute to age‐related increased reactive oxygen species (ROS) generation that plays an essential role in aging‐associated cardiac diseases. The present study investigated differences between ROS production in cardiomyocytes isolated from adult (6 months) and aged (24 months) Fischer 344 rats, and in cardiac tissue of adult (18–65 years) and elderly (>65 years) patients with preserved cardiac function. Superoxide dismutase inhibitable ferricytochrome c reduction assay (1.32±0.63 versus 0.76±0.31 nMol/mg per minute; P=0.001) superoxide and H2O2 production, measured as dichlorofluorescein diacetate fluorescence (1646±428 versus 699±329, P=0.04), were significantly higher in the aged versus adult cardiomyocytes. Similarity in age‐related alteration between rats and humans was identified in mitochondrial‐electron transport chain‐complex‐I‐associated increased oxidative‐stress by MitoSOX fluorescence (53.66±18.58 versus 22.81±12.60; P=0.03) and in 4‐HNE adduct levels (187.54±54.8 versus 47.83±16.7 ng/mg protein, P=0.0063), indicative of increased peroxidation in the elderly. These differences correlated with changes in functional enrichment of genes regulating ROS homeostasis pathways in aged human and rat hearts. Functional merged collective network and pathway enrichment analysis revealed common genes prioritized in human and rat aging‐associated networks that underlay enriched functional terms of mitochondrial complex I and common pathways in the aging human and rat heart. Aging sensitizes mitochondrial and extramitochondrial mechanisms of ROS buildup within the heart. Network analysis of the transcriptome highlights the critical elements involved with aging‐related ROS homeostasis pathways common in rat and human hearts as targets.