Abstract
Abstract 316: Transcriptional Activation of Nox1 NADPH Oxidase by Protein Disulfide Isomerase in Chronic Inflammation
Arteriosclerosis, thrombosis, and vascular biology, Vol.39(Suppl_1)
05/2019
DOI: 10.1161/atvb.39.suppl_1.316
Abstract
Abstract only Chronic inflammatory diseases are associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality as compared to the general population. For example, rheumatoid arthritis (RA) increases the risk of cardiovascular mortality by 50%, and cardiovascular disease (CVD) is the leading cause of death in RA patients. Disease-modifying anti-rheumatic therapies have pro-atherogenic effects and are associated with increased cardiovascular risk. Alternative approaches to targeting the vascular effectors of chronic inflammation may significantly improve patient health. We have previously reported that NADPH oxidase 1 (Nox1) expression is increased in atherosclerotic aorta, is proinflammatory, stimulates cell migration, and contributes to atherosclerosis lesion formation. We have also shown that protein disulfide isomerase (PDI) facilitates Nox1 activation. Here, we hypothesize that chronic inflammation increases vascular PDI expression and promotes vascular disease by enhancing Nox1 expression and activity. Aorta isolated from a murine model of inflammatory arthritis (K/BxN) demonstrated increased expression of Nox1 (p<0.05), PDI (p<0.05), tumor necrosis factor-α (p<0.05) and monocyte chemoattractant protein-1 (p<0.05). Overexpression of PDI in cultured vascular smooth muscle cells (SMCs) increased Nox1 expression by 2-fold. Mutation of PDI redox cysteines did not alter its ability to increase Nox1 expression. PDI overexpression increased the migration of SMC by 52%, and NFKB activation by 45% after agonist treatment. To measure Nox1 transcription activity, we co-transfected Nox1 promoter-luciferase with pSV40-Renilla control vectors into cultured SMCs and measured luciferase activity with the Dual-Luciferase Reporter Assay System. We found that PDI expression increased Nox1 promoter activity. Site specific mutations in the Nox1 promoter identified important transcriptional regulatory motifs. These data support a mechanism by which PDI activates Nox1 transcription independently of its oxidoreductase activity and identifies a novel mechanism for accelerated CVD in chronic inflammation.
Details
- Title: Subtitle
- Abstract 316: Transcriptional Activation of Nox1 NADPH Oxidase by Protein Disulfide Isomerase in Chronic Inflammation
- Creators
- Simone M SartorettoBrandon M SchicklingLaurynn GarciaJennifer L LucittiFrancis J Miller
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.39(Suppl_1)
- DOI
- 10.1161/atvb.39.suppl_1.316
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2019
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9984966724102771
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