Carnitine-mediated improved response to erythropoietin involves induction of haem oxygenase-1: studies in humans and in an animal model.
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.
Calò
Lorenzo A
LA
Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. renzcalo@unipd.it
Davis
Paul A
PA
Pagnin
Elisa
E
Bertipaglia
Lara
L
Naso
Agostino
A
Piccoli
Antonio
A
Corradini
Robert
R
Spinello
Michela
M
Savica
Vincenzo
V
Dalla Libera
Luciano
L
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
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