title: Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein.
abstract: OBJECTIVE
  To investigate which endothelin receptors mediated isoproterenol (ISO)-induced downregulation of FKBP12.6/12 in cardiomyocytes and study whether argirhein, a novel compound containing rhein and L-arginine that has anti-inflammatory activity, could reverse the downregulation of FKBP12.6/12 induced by ISO.
  
  
  METHODS
  Neonatal rat cardiomyocytes were incubated with ISO to downregulate FKBP12.6/12. Then the cells were treated with a selective ET(A) blocker (PD156707) and a ET(B) blocker (IRL1038), a dual ET(A)/ET(B) antagonist (CPU0213), and argirhein, respectively. FKBP12.6/12 expression was assayed by RT-PCR, Western blot, and immunocytochemistry.
  
  
  RESULTS
  The expression of FKBP12.6 mRNA was reduced by 37.7% (P<0.01) and 28.9% (P<0.05) relative to the control by ISO 1 and 0.1 μmol/L, respectively, but no response to ISO 0.01 μmol/L was observed in vitro. FKBP12.6/12 protein expression was reduced by 47.2% (P<0.01) and 37.8% (P<0.05) by ISO 1 and 0.1 μmol/L, respectively. This decrease was reversed significantly by PD156707, or IRL1038, and CPU0213. CPU0213 was more potent than either PD156707 or IRL-1038. Argirhein 10 μmol/L blunted the downregulation of FKBP12.6/12 by ISO, as demonstrated by the rising mRNA and protein levels and by the fluorescent density of the ISO-incubated cardiomyocytes.
  
  
  CONCLUSIONS
  In cardiomyocytes, the ISO induced downregulation of FKBP12.6/12 is modulated by both ET(A) and ET(B). A new compound, argirein, reversed the down-regulation of FKBP12.6/12 expression in myocardial cells stimulated with ISO.
authors.affiliation: China Pharmaceutical University, Nanjing, China.
authors.forename: Guo-lin
authors.initials: GL
authors.lastname: Zhang
authors.forename: De-zai
authors.initials: DZ
authors.lastname: Dai
authors.forename: Tao
authors.initials: T
authors.lastname: Xi
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Cong
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000880:Anthraquinones / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D007545:Isoproterenol / Q000008:administration & dosage / Q000633:toxicity; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022061:Tacrolimus Binding Protein 1A / Q000187:drug effects* / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000187:drug effects* / Q000235:genetics
chemical_list: D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C558481:argirhein; D022061:Tacrolimus Binding Protein 1A; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D007545:Isoproterenol