title: Melatonin attenuates postmyocardial infarction injury via increasing Tom70 expression.
abstract: Mitochondrial dysfunction leads to reactive oxygen species (ROS) overload, exacerbating injury in myocardial infarction (MI). As a receptor for translocases in the outer mitochondrial membrane (Tom) complex, Tom70 has an unknown function in MI, including melatonin-induced protection against MI injury. We delivered specific small interfering RNAs against Tom70 or lentivirus vectors carrying Tom70a sequences into the left ventricles of mice or to cultured neonatal murine ventricular myocytes (NMVMs). At 48 h post-transfection, the left anterior descending coronary arteries of mice were permanently ligated, while the NMVMs underwent continuous hypoxia. At 24 h after ischemia/hypoxia, oxidative stress was assessed by dihydroethidium and lucigenin-enhanced luminescence, mitochondrial damage by transmission electron microscopy and ATP content, and cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling and caspase-3 assay. At 4 weeks after ischemia, cardiac function and fibrosis were evaluated in mice by echocardiography and Masson's trichrome staining, respectively. Ischemic/hypoxic insult reduced Tom70 expression in cardiomyocytes. Tom70 downregulation aggravated post-MI injury, with increased mitochondrial fragmentation and ROS overload. In contrast, Tom70 upregulation alleviated post-MI injury, with improved mitochondrial integrity and decreased ROS production. PGC-1α/Tom70 expression in ischemic myocardium was increased with melatonin alone, but not when combined with luzindole. Melatonin attenuated post-MI injury in control but not in Tom70-deficient mice. N-acetylcysteine (NAC) reversed the adverse effects of Tom70 deficiency in mitochondria and cardiomyocytes, but at a much higher concentration than melatonin. Our findings showed that Tom70 is essential for melatonin-induced protection against post-MI injury, by breaking the cycle of mitochondrial impairment and ROS generation.
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Pei
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Juan-Ni
authors.initials: JN
authors.lastname: Hou
authors.affiliation: Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Fei-Peng
authors.initials: FP
authors.lastname: Wei
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xue
authors.affiliation: Department of Nephrology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang, China.
authors.forename: Cheng-Fei
authors.initials: CF
authors.lastname: Peng
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Lei
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Xiu-Chuan
authors.initials: XC
authors.lastname: Li
authors.affiliation: Center of Translational Medicine, Temple University School of Medicine, Philadelphia, USA.
authors.forename: Er-He
authors.initials: EH
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: De
authors.lastname: Li
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu, China.
authors.forename: Yong-Jian
authors.identifier: http://orcid.org/0000-0003-1268-166X
authors.initials: YJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D017382:Reactive Oxygen Species; C559261:Tom70 protein, mouse; D008550:Melatonin
keywords: Tom70; melatonin; mitochondria; myocardial infarction; reactive oxygen species