title: CPUY11018, an azimilide derivative, ameliorates isoproterenol-induced cardiac insufficiency through relieving dysfunctional mitochondria and endoplasmic reticulum.
abstract: OBJECTIVE
  Deterioration of cardiac performance under stress may be partly mediated by dysfunctional mitochondria and endoplasmic reticulum (ER) that is likely related to an activation of NADPH oxidase (NOX) and an increase in pro-inflammatory factors. We investigated if a new compound CPUY11018 (CPUY) derived from Azimilide could ameliorate the stress impaired cardiac performance.
  
  
  METHODS
  Forty-eight male Sprague Dawley rats were randomly divided into six groups and were injected with isoproterenol (ISO, 1 ml/kg, s.c.) for 10 days. Cardiac myocytes and fibroblasts from neonate rats were incubated with ISO. CPUY was employed and compared with apocynin (APO) - an inhibitor of NOX.
  
  
  RESULTS
  In ISO-treated group, the compromised haemodynamics and cardiac remodelling were significant with dysfunctional mitochondria indicated by decreased MnSOD and mitochondrial membrane potential, and an enhanced reactive oxygen species genesis. Downregulation of FKBP12.6, CASQ2 and SERCA2a was also remarkable in vivo and in vitro implying an abnormal ER. Upregulated Nox4, p22(phox) and p47(phox) were significant, associated with upregulation of Src, IκBβ and NFκB, and downregulation of pAMPK/AMPK and Cx40 in vivo and in vitro. These abnormalities were relieved by CPUY and APO.
  
  
  CONCLUSIONS
  CPUY is potential in managing cardiac insufficiency through normalizing mitochondria and ER in the affected heart.
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, The Medical School, University of Nanjing, Nanjing, China.
authors.forename: Rong-Hui
authors.initials: RH
authors.lastname: Du
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Fang-Hong
authors.initials: FH
authors.lastname: Shi
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.|Pharmacology Department, Faculty of Pharmacy, University of Aden, Aden, Yemen.
authors.forename: Humed Khan
authors.initials: HK
authors.lastname: Hussein
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000096:biosynthesis; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy*; D006439:Hemodynamics; D006827:Hydantoins / Q000494:pharmacology*; D006835:Hydrazones / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C000606703:1-(2,3-dihydro-6-propoxychromen-4-ylideneamino)-3-(3-(4-methylpiperazin-1-yl)propyl)imidazolidine-2,4-dione; D000098:Acetophenones; D015415:Biomarkers; D002317:Cardiovascular Agents; D002352:Carrier Proteins; D006827:Hydantoins; D006835:Hydrazones; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; C056165:acetovanillone; D019255:NADPH Oxidases; D007545:Isoproterenol
keywords: CPUY11018; NFκB; endoplasmic reticulum; mitochondria; nicotinamide adenine dinucleotide phosphate oxidase