Department of Biophysics, Ankara University, Faculty of Medicine, Ankara, Turkey.
Department of Histology-Embriology, Ankara University, Faculty of Medicine, Ankara, Turkey.
Exp Gerontol. 2018 Sep;110:172-181. doi: 10.1016/j.exger.2018.06.012. Epub 2018 Jun 13.
Aging in humans represents declining in cardio-protective systems, however its mechanisms are not known yet. We aimed to analyse how aging affects key mechanisms responsible for contractile dysfunction via comparing the improperly synchrony between electrical and mechanical activities in male aged-rats (24-month old) comparison to those of adult-rats (6-month old). We determined significantly increased systemic oxidative stress with decreased antioxidant capacity, clear insulin resistance and hypertrophy in aged-rats with normal fasting blood glucose. We also determined significantly high level of reactive oxygen species, ROS production in fluorescent dye chloromethyl-2',7'-dichlorodihydrofluoroscein diacetate (DCFDA) loaded isolated cardiomyocytes from aged-rats, confirming the increased oxidative stress in these hearts. In situ electrocardiograms, ECGs presented significant prolongations in RR- and QT-intervals in the aged-rats. Invasive hemodynamic measurements demonstrated marked increases in the heart rate and mean arterial pressure and decreases in the ejection-fraction and preload-recruitable stroke-work, together with depressed contraction and relaxation activities in aortic rings. In light and electron microscopy examinations in aged-rats, significant increases in muscle fibre radius and amount of collagen fibres were detected in the heart as well as markedly flattened and partial local splitting in elastic lamellas in the aorta, besides irregularly clustered mitochondria and lysosomes around the myofilaments in cardiomyocytes. MitoTEMPO treatment of tissue samples and cardiomyocytes from aged-rats for 1-h induced significant structural improvements. In the second part of our study, we have shown that mitochondria-targeted antioxidant MitoTEMPO antagonized all alterations in the heart samples as well as penylephrine-induced contractile and acetylcholine-induced relaxation responses of aged-rat aortic rings. Overall, the present data strongly support the important role of mitochondrial oxidative stress in the development of aged-related insufficiencies and that antioxidant strategies specifically targeting this organelle could have therapeutic benefit in aging-associated complications.
人类衰老表现为心脏保护系统的衰退，但衰老的机制尚不清楚。我们旨在通过比较老年大鼠（24 个月龄）与成年大鼠（6 个月龄）心肌电-机械活动之间的不协调，分析衰老如何影响导致收缩功能障碍的关键机制。我们发现，尽管空腹血糖正常，但老年大鼠表现出系统性氧化应激增加、抗氧化能力降低、明确的胰岛素抵抗和心肌肥厚。我们还发现，从老年大鼠分离的心肌细胞中，荧光染料氯甲基-2',7'-二氯二氢荧光素二乙酸酯（DCFDA）负载的活性氧物种（ROS）产生显著增加，证实这些心脏中的氧化应激增加。在体心电图（ECG）显示老年大鼠的 RR 和 QT 间期显著延长。有创血流动力学测量显示，老年大鼠的心率和平均动脉压显著增加，射血分数和预负荷可收缩功降低，主动脉环的收缩和舒张活动减弱。在老年大鼠的光镜和电镜检查中，发现心脏中的肌纤维半径和胶原纤维数量显著增加，主动脉中的弹性膜明显变平且部分局部分裂，此外，心肌细胞中的线粒体和溶酶体不规则聚集在线粒体周围。用 MitoTEMPO 处理老年大鼠的组织样本和心肌细胞 1 小时可显著改善结构。在我们研究的第二部分，我们表明，线粒体靶向抗氧化剂 MitoTEMPO 拮抗了心脏样本中的所有改变，以及去甲肾上腺素诱导的老年大鼠主动脉环收缩反应和乙酰胆碱诱导的舒张反应。总的来说，这些数据强烈支持线粒体氧化应激在衰老相关缺陷发展中的重要作用，并且专门针对该细胞器的抗氧化策略可能对与衰老相关的并发症具有治疗益处。
