title: N-n-butyl haloperidol iodide protects cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy.
abstract: N-n-butyl haloperidol iodide (F2), a novel compound derived from haloperidol, protects against the damaging effects of ischemia/reperfusion (I/R) injury in vitro and in vivo. In this study, we hypothesized the myocardial protection of F2 on cardiomyocyte hypoxia/reoxygenation (H/R) injury is mediated by inhibiting autophagy in H9c2 cells. The degree of autophagy by treatment with F2 exposed to H/R in H9c2 cell was characterized by monodansylcadaverine, transmission electron microscopy, and expression of autophagy marker protein LC3. Our results indicated that treatment with F2 inhibited autophagy in H9c2 cells exposed to H/R. 3-methyladenine, an inhibitor of autophagy, suppressed H/R-induced autophagy, and decreased apoptosis, whereas rapamycin, a classical autophagy sensitizer, increased autophagy and apoptosis. Mechanistically, macrophage migration inhibitory factor (MIF) was inhibited by F2 treatment after H/R. Accordingly, small interfering RNA (siRNA)-mediated MIF knockdown decreased H/R-induced autophagy. In summary, F2 protects cardiomyocytes during H/R injury through suppressing autophagy activation. Our results provide a new mechanistic insight into a functional role of F2 against H/R-induced cardiomyocyte injury and death.
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, 515041 Guangdong, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital, Shantou University Medical College, Shantou, 515041 Guangdong, China.
authors.forename: Fuchun
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, 515041 Guangdong, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, 515041 Guangdong, China.
authors.forename: Fenfei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, 515041 Guangdong, China.
authors.forename: Yicun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, 515041 Guangdong, China.
authors.forename: Binger
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, 515041 Guangdong, China.
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Shantou University Medical College, Shantou, 515041 Guangdong, China.|Department of Cardiovascular Diseases, The First Affiliated Hospital, Shantou University Medical College, Shantou, 515041 Guangdong, China.
authors.forename: Ganggang
authors.initials: G
authors.lastname: Shi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002103:Cadaverine / Q000031:analogs & derivatives / Q000378:metabolism; D002460:Cell Line; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D020011:Protective Agents / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection
chemical_list: D000225:Adenine; D002103:Cadaverine; D006220:Haloperidol; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D008869:Microtubule-Associated Proteins; D020011:Protective Agents; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C526109:Anxa3 protein, rat; C482574:N-n-butyl haloperidol iodide; C025946:3-methyladenine; C546845:mTOR protein, rat; C515599:Mif protein, rat; C008542:monodansylcadaverine
keywords: N-n-butyl haloperidol iodide; Pathology Section; apoptosis; autophagy; cardiomyocytes; hypoxia/reoxygenation