title: Melatonin prevents adverse myocardial infarction remodeling via Notch1/Mfn2 pathway.
abstract: Mitochondrial dysfunction is linked with myocardial infarction (MI), a disorder in which Notch1 has attracted increasing attention. However, the involvement of Notch1 in mitochondrial impairment after an MI is poorly understood, as is the role of mitochondrial fusion-associated protein 2 (Mfn2). Moreover, whether melatonin potentiates the Notch1/Mfn2 pathway in post-MI cardiac damage remains unclear. In our study, small interfering RNAs against Notch1 or Mfn2 and Jagged1 peptide were delivered via intramyocardial injection. At 3 days after these treatments, MI was induced by ligation of the anterior descending branch. We found that this ablation of Notch1 or Mfn2 aggravated post-MI injury, including worsened mitochondrial damage and increased generation of reactive oxygen species (ROS). In contrast, Jagged1 improved mitochondrial structure and function, decreased ROS production and attenuated post-MI injury. Interestingly, though Mfn2 expression was mildly regulated by Notch1 signaling in myocardium, Mfn2 deficiency nearly eliminated the cardioprotection by Jagged1, as evidenced by suppressed cardiac function, aggravated myocardial fibrosis, increased cell apoptosis, worsened mitochondrial impairment and enhanced oxidative stress. These observations revealed that Mfn2 plays an indispensable role in protection against MI-induced injury by Notch1. The mechanism might involve disrupting a damaging cycle of mitochondrial damage and ROS generation. Furthermore, melatonin activated Notch1 signaling and increased Mfn2 expression were reversed by luzindole, a nonselective antagonist of the melatonin receptor. Notably, melatonin attenuated post-MI injury in normal mice, but not in mice deficient in Notch1 or Mfn2. These results demonstrate that melatonin attenuates post-MI injury via the Notch1/Mfn2 pathway in a receptor-dependent manner.
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China; Third Military Medical University, Chongqing 400042, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Pei
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Lei
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Medical Genetics and Developmental Biology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Xiuchuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Chenming
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Juanni
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Center of Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: De
authors.lastname: Li
authors.affiliation: Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China; Third Military Medical University, Chongqing 400042, China. Electronic address: yyj10001@126.com.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D000072100:Jagged-1 Protein / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; D008550:Melatonin
keywords: Melatonin; Mfn2; Mitochondria; Myocardial infarction; Notch1; ROS