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J Immunol. 2017 Sep 15;199(6):1979-1988. doi: 10.4049/jimmunol.1600108. Epub 2017 Aug 4.

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

Author information

1
Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425.
2
Department of Molecular and Cellular Biology and Pathobiology, Medical University of South Carolina, Charleston, SC 29425.
3
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425; and.
4
Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; oatesjc@musc.edu.
5
Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401.

Abstract

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

PMID:
28779021
PMCID:
PMC5587385
DOI:
10.4049/jimmunol.1600108
[Indexed for MEDLINE]
Free PMC Article

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