title: Lipoxin A4-induced heme oxygenase-1 protects cardiomyocytes against hypoxia/reoxygenation injury via p38 MAPK activation and Nrf2/ARE complex.
abstract: OBJECTIVE
  To investigate whether lipoxin A4 (LXA4) increases expression of heme oxygenase-1(HO-1) in cardiomyocytes, whether LXA4-induced HO-1 protects cardiomyocytes against hypoxia/reoxygenation (H/R) injury, and what are the mechanisms involved in the LXA4-induced HO-1 induction.
  
  
  METHODS
  Rat cardiomyocytes were exposed to H/R injury with or without preincubation with LXA4 or HO-1 inhibitor ZnPP-IX or various signal molecule inhibitors. Expressions of HO-1 protein and mRNA were analyzed by using Western blot and RT-PCR respectively. Activity of nuclear factor E2-related factor 2 (Nrf2) binding to the HO-1 E1 enhancer was assessed by chromatin immunoprecipitation. Nrf2 binding to the HO-1 antioxidant responsive element (ARE) were measured by using electrophoretic mobility shift assay.
  
  
  RESULTS
  Pretreatment of the cells undergoing H/R lesion with LXA4 significantly reduced the lactate dehydrogenase and creatine kinase productions, increased the cell viability, and increased the expressions of HO-1 protein and mRNA and HO-1 promoter activity. HO-1 inhibition abolished the protective role of LXA4 on the cells undergoing H/R lesion. LXA4 increased p38 mitogen-activated protein kinase (p38 MAPK) activation, nuclear translocation of Nrf2, Nrf2 binding to the HO-1 ARE and E1 enhancer in cardiomyocytes with or without H/R exposure.
  
  
  CONCLUSIONS
  The protection role of LXA4 against H/R injury of cardiomyocytes is related to upregulation of HO-1, via activation of p38 MAPK pathway and nuclear translocation of Nrf2 and Nrf2 binding to the HO-1 ARE and E1 enhancer, but not via activation of phosphatidyinositol-3-kinase or extracellular signal-regulated kinase pathway.
authors.affiliation: Department of Pediatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Chen
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Wu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yan-Rong
authors.initials: YR
authors.lastname: Tang
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics*; D002316:Cardiotonic Agents / Q000494:pharmacology; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D000860:Hypoxia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D044045:Lipoxins / Q000494:pharmacology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D044045:Lipoxins; D051267:NF-E2-Related Factor 2; C040527:lipoxin A4; D007770:L-Lactate Dehydrogenase; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D003402:Creatine Kinase; D010100:Oxygen