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

Abstract

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.

New Insights into Nephrogenic Systemic Fibrosis

“…46,49 It can also induce endothelial dysfunction by inhibiting dimethylarginine dimethylaminohydrolase, thereby increasing asymmetric dimethyl arginine. 50 Furthermore, EPO is a potent stimulant of endothelial and progenitor cell proliferation, 51,52 as well as wound-healing responses 53 that are reminiscent of histologic 45,47 might also contribute to the fibrogenesis seen in NSF.…”

“…Theoretically, EPO therapy influences all key elements of the pathogenesis of NSF: Endothelial dysfunction, inflammation, cell proliferation, and wound healing. EPO is a potent cytokine with stimulatory effects on vascular endothelium, 43 smooth muscle cells, 44,45 and platelets. 46 EPO administration induces a release of vasoactive factors such as monocyte chemoattractant protein-1, 45,47 endothelin-1, 48 thromboxane A2, and selectin.…”

Oxide in hemodialysis patients

“…According to a 2006 study by Desai et al, a 24 hour incubation of human aortic endothelial cells with rhEpo results in a downregulation of endothelial NOS protein expression. Thus, rhEpo significantly reduces NO production by both quiescent and proliferating endothelial cells (18). However, some studies indicate that prolonged rhEpo supplementation therapy may cause adverse effects due to its effect on NO.…”

Dual Delivery of EPO and BMP2 from a Novel Modular Poly-ɛ-Caprolactone Construct to Increase the Bone Formation in Prefabricated Bone Flaps

“…16 In this study, endothelial cell proliferation was used to indicate EPO bioactivity as done in other studies. [30][31][32] A disc geometry with a flat surface was used for this assay due to a welldefined surface area and a simple geometry. This assay's goal was to assess the protein's bioactivity and not the extent of bioactivity.…”