IFN-α Negatively Regulates the Expression of Endothelial Nitric Oxide Synthase and Nitric Oxide Production: Implications for Systemic Lupus Erythematosus

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.

Endothelial cell functions impaired by interferon in vitro: Insights into the molecular mechanism of thrombotic microangiopathy associated with interferon therapy

“…As expected, we observed that VEGF caused an enhancement in NO production in HUVECs. However, endothelial production of NO was reduced by IFN treatment, which is in agreement with a very recent report that IFN-α inhibits NO production in HUVECs [43]. Vascular homeostasis is achieved through the finetuned regulation of the integrity of the endothelial cell monolayer by vasoactive modulators, and a proper amount of NO is essential for correct endothelial functioning.…”

Interferon pathway in SLE: one key to unlocking the mystery of the disease

“…The type I IFNs also have effects outside the immune system, such as impairment of endothelium-dependent vasorelaxation and endothelial progenitor cell function, which slow down the repair process of damaged endothelium 84–86. Further, IFN-α inhibits eNOS expression and impairs insulin-mediated nitric oxide production in endothelial cells,87 enhances foam cell formation88 and alters platelet function 89. These observations can be linked to the unexpectedly high prevalence of atherosclerosis and cardiovascular disease in patients with SLE 90.…”

Role of the eNOS Uncoupling and the Nitric Oxide Metabolic Pathway in the Pathogenesis of Autoimmune Rheumatic Diseases

“…Continuous inflammatory production of interferon-alpha (IFN-α) and subsequent increased expression of IFN-α-regulated genes, referred as IFN signature, due to activation of plasmacytoid dendritic cells by immune complexes, consisting of autoantibodies in combination with deoxyribonucleic acid-(DNA-) or ribonucleic acid-(RNA-) containing autoantigens, have been reported in SLE patients. Studies on animals and humans have provided evidence that IFN accelerate atherosclerosis on multiple stages [149][150][151].…”

“…To date, no studies were conducted to determine direct effects of IFN on eNOS function and NO generation. However, IFN type I has been reported to have impact on enzyme cofactors, its specific transcription factors, and oxidative stress pathways [151]. Animal and human studies indicate that IFN-α leads to depletion of BH 4 via oxidation, serving as a potential mediator of eNOS uncoupling and oxidative stress [152,153].…”