Naaz Shamreen, Mishra Sanatan, Pal Palash K, Chattopadhyay Aindrila, Das Asish R, Bandyopadhyay Debasish
Department of Physiology, Oxidative Stress and Free Radical Biology Laboratory, University of Calcutta, University College of Science and Technology, 92, APC Road, Kolkata 700 009, West Bengal, India.
Department of Physiology, Vidyasagar College for Women, Kolkata 700 006, India.
Heliyon. 2020 Oct 13;6(10):e05159. doi: 10.1016/j.heliyon.2020.e05159. eCollection 2020 Oct.
Preventing mitochondrial dysfunction and enhancing mitochondrial health and biogenesis is a crucial therapeutic approach to ameliorate injury following acute myocardial infarction. Although the antioxidant role of melatonin against ischemia/reperfusion injury has been reported, the exact mechanism of protection, , remains poorly understood. This study aims to identify and elaborate upon mechanism of melatonin protection of rat cardiac mitochondria against acute myocardial infarction.
Rats were pre-treated with melatonin (10 mg/kg body weight (b.w.); intraperitoneally, i.p.) before isoproterenol bitartrate (ISO) administration (25 mg/kg body weight (b.w.) subcutaneously,s.c.) and their effect on rat heart mitochondrial structure and function was studied. Biochemical changes in activity of biomarkers of oxidative stress, antioxidant enzymes as well as Krebs' cycle enzymes were analyzed. Gene expression studies and Isothermal titration calorimetric studies with pure catalase and ISO were also carried out.
Melatonin was shown to reduce ISO induced oxidative stress, by stimulating superoxide dismutase activity and removing the inhibition of Krebs' cycle enzymes. Herein we report for the first time in rat model that melatonin activates the SIRT1-PGC-1α-SIRT3 signaling pathways after ISO administration, which ultimately induces mitochondrial biogenesis. Melatonin exhibited significant protection of mitochondrial architecture and topology along with increased calcium ion permeability and reactive oxygen species (ROS) generation induced by ISO. Isothermal calorimetric studies revealed that melatonin binds to ISO molecules and sequesters them from the reaction thereby limiting their interaction with catalase along with occupying the binding sites of catalase themselves.
Activation of SIRT1-PGC-1α-SIRT3 pathway by melatonin along with its biophysical properties prevents ISO induced mitochondrial injury in rat heart.
预防线粒体功能障碍，增强线粒体健康和生物合成，是改善急性心肌梗死后损伤的关键治疗方法。尽管已报道褪黑素对缺血/再灌注损伤具有抗氧化作用，但其确切的保护机制仍知之甚少。本研究旨在确定并阐述褪黑素对大鼠心脏线粒体免受急性心肌梗死的保护机制。
在给予酒石酸异丙肾上腺素（ISO，25mg/kg体重，皮下注射）之前，用褪黑素（10mg/kg体重，腹腔注射）对大鼠进行预处理，并研究其对大鼠心脏线粒体结构和功能的影响。分析氧化应激生物标志物、抗氧化酶以及三羧酸循环酶活性的生化变化。还进行了基因表达研究以及用纯过氧化氢酶和ISO进行的等温滴定量热研究。
褪黑素通过刺激超氧化物歧化酶活性和消除对三羧酸循环酶的抑制，显示出可减轻ISO诱导的氧化应激。在此我们首次在大鼠模型中报道，褪黑素在给予ISO后激活SIRT1-PGC-1α-SIRT3信号通路，最终诱导线粒体生物合成。褪黑素对线粒体结构和拓扑结构具有显著保护作用，同时增加了ISO诱导的钙离子通透性和活性氧（ROS）生成。等温量热研究表明，褪黑素与ISO分子结合并将它们从反应中隔离，从而限制它们与过氧化氢酶的相互作用，同时占据过氧化氢酶自身的结合位点。
褪黑素激活SIRT1-PGC-1α-SIRT3通路及其生物物理特性可预防ISO诱导的大鼠心脏线粒体损伤。
