title: HIF-1alpha accumulation upregulates MICA and MICB expression on human cardiomyocytes and enhances NK cell cytotoxicity during hypoxia-reoxygenation.
abstract: OBJECTIVE
  To investigate whether hypoxia-inducible factor (HIF) 1alpha and cyclosporin A (CsA) can regulate MICA/B expression and affect NK cytotoxicity during ischemia/reperfusion (I/R) injury.
  
  
  METHODS
  We generated an HIF-1alphaDeltaODD-expressing adenovirus which can functionally and steadily express HIF-1alpha during normoxia and transfected human cardiomyocytes (HCMs) to investigate whether HIF-1alpha, as a single factor, can upregulate MICA/B expression. Alternatively, HCMs were treated with HIF-1alpha RNAi or CsA, and then cultured under hypoxia/reoxygenation (H/R) condition to simulate I/R injury in vitro. Cells were collected at different time points and used for studies of gene expression and NK cytotoxicity.
  
  
  RESULTS
  Expression of MICA/B in HCMs is upregulated through HIF-1alpha overexpression in normoxia, and inhibited by HIF-1alpha RNAi treatment during hypoxia-reoxygenation (H/R). NK cytotoxicity towards HCMs shows a positive correlation with HIF-1alpha expression. Moreover, CsA can inhibit HIF-1alpha and MICB expression but upregulates MICA expression during H/R.
  
  
  CONCLUSIONS
  These findings suggest that proper control of HIF-1alpha expression via CsA dose may be a potential therapeutic approach for avoiding MIC expression, and improving the function and long-term survival of heart allografts.
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology of Health Ministry of China, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wei
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.forename: Dan
authors.initials: D
authors.lastname: Long
authors.forename: Juan
authors.initials: J
authors.lastname: Shan
authors.forename: Shengfu
authors.initials: S
authors.lastname: Li
authors.forename: Youping
authors.initials: Y
authors.lastname: Li
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology*; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D034622:RNA Interference; D015427:Reperfusion Injury / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015395:Histocompatibility Antigens Class I; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007166:Immunosuppressive Agents; C099187:MHC class I-related chain A; C098080:MICB antigen; D016572:Cyclosporine; D010100:Oxygen