Article Text

ERYTHROPOIETIN INDUCES WHILE HEME OXYGENASE INHIBITS MOBILIZATION OF ENDOTHELIAL PROGENITOR CELLS IN FLOW-ASSOCIATED PULMONARY ARTERIAL HYPERTENSION IN RATS
  1. N Affara1,
  2. R L E van Loon1,
  3. M E van Albada1,
  4. B Bartelds1,
  5. R M F Berger1
  1. 1Department of Pediatric Cardiology, Beatrix Children’s Hospital-UMCG, Groningen, The Netherlands

Abstract

Introduction Pulmonary arterial hypertension (PAH) is characterized by advanced pulmonary vascular lesions. Erythropoietin (EPO) mobilizes endothelial progenitor cells (EPCs) that may participate in the repair of these pulmonary vascular lesions, possibly via activation of Heme Oxygenase-1 (HO-1). HO-1 is an inducible enzyme with anti-oxidant and anti-apoptotic activities. To test the hypothesis that Epo induces mobilization of EPCs via HO-1, we treated rats with flow-associated PAH with Epo in combination with a blocker of HO-1 (SnMP).

Materials and Method PAH was created in male Wistar rats by injection of monocrotaline (60 mg/kg) followed by an abdominal aorto-caval shunt one week later. Immediately afterwards, rats were randomized to treatment with EPO (n = 10), EPO and a HO-1 blocker (SnMP, n = 10), HO-1 blocker alone (n = 10) or no treatment (n = 10). Two and four weeks later, EPCs were isolated from peripheral blood and stained.

Results Epo treatment in rats with flow-associated PAH induces EPC mobilization after 4 weeks (314±53 in PAH+EPO vs. 183±38 in PAH, p<0.001). Unexpectedly, blockade of HO-1 in combination with Epo treatment increased rather than inhibited EPC mobilization (469±39 in PAH+EPO+SnMP vs. 314±53 in PAH+EPO, p<0.001). Moreover, administration of the HO-1 blocker alone (SnMP only) also modestly but not significantly increased EPC mobilization (to 290±25, n.s.)

Conclusion In the rat model of flow-associated PAH we showed that EPO mobilizes EPCs, but the mobilization of EPCs is not via activation of HO-1. In contrast, HO-1 appears to be a negative regulator of EPC mobilization.

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