Role of heme oxygenase-1 and endothelial progenitor cells in the beneficial effects of erythropoietin on flow-associated pulmonary arterial hypertension

  • Rosa Laura van Loon, Department of Pediatric Cardiology, University Medical Center Groningen, Groningen, The Netherlands
  • Beatrijs Bartelds, Department of Pediatric Cardiology, University Medical Center Groningen, University of Groningen, Groningen(, The Netherlands
  • Frank Wagener, Department of Pharmacology and Toxicology, Nijmegen Center for Molecular Life Sciences, University Nijmegen Medical Center, The Netherlands
  • Mirjam van Albada, Department of Pediatric Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  • Nada Affara, Department of Pediatric Cardiology, University Medical Center Groningen, Groningen, The Netherlands
  • Hans Wijnberg, Department of Pediatric Cardiology, University Medical Center Groningen, Groningen, The Netherlands
  • Saffloer Mohaupt, Department of Pediatric Cardiology, University Medical Center Groningen, Groningen, The Netherlands
  • Rolf M Berger, Department of Pediatric Cardiology, University Medical Center Groningen, Groningen, The Netherlands

    • Objectives
    We previously reported that erythropoietin(EPO) improves pulmonary vascular remodeling in rats with flow-associated pulmonary arterial hypertension(PAH). To test the hypothesis that EPO improves this remodeling through activation of heme oxygenase-1 (HO-1) and mobilization of endothelial progenitor cells (EPCs), we treated these rats with EPO with and without a HO-activity blocker (SnMP).
    Methods
    Flow-associated PAH was created in rats by injection of monocrotaline followed by an abdominal aorto-caval shunt. Rats were randomized to EPO (PAH+EPO,n=14), EPO+SnMP (PAH+EPO+SnMP,n=13), SnMP (PAH+SnMP,n=11) or no treatment (PAH,n=14). Three weeks later, hemodynamics, pulmonary vascular remodeling, number of EPCs in peripheral blood and pulmonary HO-activity were evaluated.
    Results
    Compared to PAH, wall thickness of small pulmonary vessels decreased after EPO, increased after EPO+SnMP and increased even more after SnMP treatment (Figure).
    Number of EPCs increased after EPO and SnMP and increased even further after EPO+SnMP treatment. Pulmonary HO-activity remained stable after EPO and decreased after SnMP and EPO+SnMP. Pulmonary arterial pressure and right ventricular contractility remained unchanged.
    Conclusion
    In this rat model of flow-associated PAH, EPO improved pulmonary vascular remodeling, increased the number of EPCs in peripheral blood, but did not increase pulmonary HO-activity. HO-activity blockade alone worsened pulmonary vascular remodeling, while increasing the number of EPCs. This indicates that both EPO and HO have beneficial effects on PAH, however, mediated via different mechanisms. The beneficial effects of EPO do not seem mediated by increased HO-activity. Our data suggest, however, that HO may facilitate the homing of circulating EPCs to the diseased pulmonary vascular bed.