title: Carnitine-mediated improved response to erythropoietin involves induction of haem oxygenase-1: studies in humans and in an animal model.
abstract: BACKGROUND
  Carnitine improves erythropoetin (EPO) response and anaemia in haemodialysis patients (HD); however, the mechanism(s) responsible remain unidentified. We have reported that carnitine induces haem oxygenase (HO)-1, which is an antioxidant and antiapoptotic that acts via pathways shared with EPO. Therefore carnitine's effect on these pathways may account for the improved EPO response. This study evaluates carnitine's effect on protein expression of HO-1 in unexplained EPO resistant HD. Carnitine's effect was assessed by HO-1 expression in patients and compared to its antiapoptotic effect via HO-1 induction in a rat model of carnitine-treated heart failure.
  
  
  METHODS
  Unexplained EPO resistant HD mononuclear cell HO-1 and rat gastrocnemious muscle HO-1 and Bcl-2 protein expression were evaluated by western blot.
  
  
  RESULTS
  HD's haemoglobin (Hb) and haematocrit (Ht) were not different before carnitine treatment: 8.8 +/- 0.4 mg/dl versus 8.98 +/- 0.13 and 30.20% +/- 0.84 versus 30.72 +/- 1.14, respectively. Carnitine increased HO-1, Hb and Ht compared with patients not treated with carnitine: 2.40 +/- 0.58 versus 1.49 +/- 0.41, P = 0.02; 11.22 +/- 0.54 versus 8.90 +/- 0.15, P < 0.0001; 32.72 +/- 1.77 versus 30.66 +/- 0.43, P = 0.035, respectively. Carnitine-treated HD's HO-1 significantly correlated with haemoglobin. HO-1 and Bcl-2 protein levels in untreated heart failure rat's gastrocnemious muscle were reduced when compared with controls: 3.41 +/- 0.49 versus 5.32 +/- 0.38 and 0.69 +/- 0.11 versus 1.65 +/- 0.37, respectively, but were higher in carnitine-treated heart failure rats: 4.8 +/- 0.32 versus 3.41 +/- 0.49, P < 0.0002 and 1.09 +/- 0.08 versus 0.69 +/- 0.11, P = 0.0007, respectively.
  
  
  CONCLUSIONS
  These results are consistent with an involvement of HO-1 in carnitine's effect on erythropoiesis. The initial signals or effectors responsible for carnitine's effect remain to be identified.
authors.affiliation: Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. renzcalo@unipd.it
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Calò
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davis
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.forename: Lara
authors.initials: L
authors.lastname: Bertipaglia
authors.forename: Agostino
authors.initials: A
authors.lastname: Naso
authors.forename: Antonio
authors.initials: A
authors.lastname: Piccoli
authors.forename: Robert
authors.initials: R
authors.lastname: Corradini
authors.forename: Michela
authors.initials: M
authors.lastname: Spinello
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Savica
authors.forename: Luciano
authors.initials: L
authors.lastname: Dalla Libera
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002331:Carnitine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology*; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006400:Hematocrit; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D006435:Renal Dialysis; D015398:Signal Transduction / Q000502:physiology
chemical_list: D006454:Hemoglobins; D019253:Proto-Oncogene Proteins c-bcl-2; D004921:Erythropoietin; D016686:Monocrotaline; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D002331:Carnitine