Research Article

Laboratory Investigation (2006) 86, 369–379. doi:10.1038/labinvest.3700396; published online 13 February 2006

Nitric oxide suppresses EPO-induced monocyte chemoattractant protein-1 in endothelial cells: implications for atherogenesis in chronic renal disease

Anjali Desai1, Ying Zhao1, Heather A Lankford1 and Jeffrey S Warren1

1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

Correspondence: Dr JS Warren, MD, Department of Pathology, University of Michigan Medical School, Box 0602, 1301 Catherine Street, Ann Arbor, MI 48109-0602, USA. E-mail:

Received 21 December 2005; Accepted 23 December 2005; Published online 13 February 2006.



Patients with advanced chronic renal disease (CRD) suffer from excessive morbidity and mortality due to complications of accelerated atherosclerosis. Approximately 90% of dialysis-dependent end stage renal disease patients suffer from anemia. Recombinant human erythropoietin (EPO) in combination with iron has become widely used to treat anemic CRD patients. While treatment with EPO results in improved quality of life it may also contribute to the development of atherosclerosis. Recent studies suggest that a reduction in nitric oxide (NO) availability may be linked to EPO-induced vascular dysfunction. Furthermore, CRD per se is thought to result in a state of NO deficiency. The present study suggests that EPO may exert proatherogenic activity by augmenting the cytokine-induced expression of monocyte-chemoattractant protein-1 (MCP-1) in human umbilical vein endothelial cells (HUVECs) and by stimulating the proliferation of HUVECs and human vascular smooth muscle cells (HVSMCs). Augmentation of MCP-1 expression appears to be linked to EPO-induced downregulation of endothelial NO synthase (ecNOS). NO released from a series of synthetic donor compounds suppressed the EPO-mediated augmentation of cytokine-induced MCP-1 expression. In vitro studies revealed that EPO reduces ecNOS expression at both the protein and mRNA levels and that EPO also mediates a reduction in ecNOS enzymatic activity. These observations suggest potential mechanisms through which EPO may contribute to the development of accelerated atherosclerosis, particularly in the setting of CRD where NO availability may already be compromised.


chronic renal disease, endothelial cells, erythropoietin, monocyte-chemoattractant protein-1, nitric oxide