title: Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling.
abstract: Enhancing mitochondrial biogenesis and reducing mitochondrial oxidative stress have emerged as crucial therapeutic strategies to ameliorate diabetic myocardial ischemia/reperfusion (MI/R) injury. Melatonin has been reported to be a safe and potent cardioprotective agent. However, its role on mitochondrial biogenesis or reactive oxygen species (ROS) production in type 1 diabetic myocardium and the underlying mechanisms remain unknown. We hypothesize that melatonin ameliorates MI/R injury in type 1 diabetic rats by preserving mitochondrial function via AMPK-PGC-1α-SIRT3 signaling pathway. Both our in vivo and in vitro data showed that melatonin reduced MI/R injury by improving cardiac function, enhancing mitochondrial SOD activity, ATP production and oxidative phosphorylation complex (II, III and IV), reducing myocardial apoptosis and mitochondrial MDA, H2O2generation. Importantly, melatonin also activated AMPK-PGC-1α-SIRT3 signaling and increased SOD2, NRF1 and TFAM expressions. However, these effects were abolished by Compound C (a specific AMPK signaling blocker) administration. Additionally, our cellular experiment showed that SIRT3 siRNA inhibited the cytoprotective effect of melatonin without affecting p-AMPK/AMPK ratio and PGC-1α expression. Taken together, we concluded that melatonin preserves mitochondrial function by reducing mitochondrial oxidative stress and enhancing its biogenesis, thus ameliorating MI/R injury in type 1 diabetic state. AMPK-PGC1α-SIRT3 axis plays an essential role in this process.
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenyang, Liaoning 110016, China.|Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu 210008, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Gong
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Weixun
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi 710032, China.
authors.forename: Chongxi
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Yinli
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Meng
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Buying
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Natural Medicine, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.lastname: Bin Zhang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Zhenxiao
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu 210008, China.|Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, 83 Wenhua Road, Shenyang, Liaoning 110016, China.
authors.forename: Huishan
authors.initials: H
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D005947:Glucose / Q000633:toxicity; D005951:Glucose Tolerance Test; D008297:Male; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D056566:Sirtuin 3 / Q000378:metabolism*; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D034741:RNA, Small Interfering; C489030:Tfam protein, rat; D014157:Transcription Factors; D013311:Streptozocin; D045304:Cytochromes c; D013482:Superoxide Dismutase; D055372:AMP-Activated Protein Kinases; D056566:Sirtuin 3; D005947:Glucose; D008550:Melatonin