No abstract

Systemic lupus erythematosus (SLE) is a known risk factor for endothelial dysfunction. Murine and human lupus studies have implicated a role for IFNα in vascular abnormalities associated with impaired blood vessel dilation. However, the impact of IFNα on mediators that induce vasodilation and modulate inflammation including endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) bioavailability are unknown. The objectives of this study were to determine how IFNα promotes endothelial dysfunction in SLE focusing on its regulation of eNOS and NO production in endothelial cells. We demonstrate that IFNα promotes an endothelial dysfunction signature in human umbilical vein endothelial cells (HUVECs), characterized by transcription suppression and mRNA instability of eNOS complemented by upregulation of MCP1 and VCAM1. These changes are associated with interferon-inducible gene expression. IFNα impairs insulin mediated NO production and Altered gene expression resulted from eNOS instability, possibly due to enhanced miR-155 expression. IFNα significantly impaired NO production in insulin stimulated HUVECs. IFNα treatment also lead to enhanced neutrophil adhesion. Our study introduces a novel pathway whereby IFNα serves as a pro-atherogenic mediator through repression of eNOS dependent pathways. This could promote development of endothelial dysfunction and cardiovascular disease in SLE.