AB0119 High Dose Glucocorticoids Are Not Deleterious for Endothelial Function in Rheumatoid Arthritis: Mechanistic Insights in Adjuvant-Induced Arthritis
Authors: F. Verhoeven, K. Maguin-Gaté, P. Totoson, C. Prati, D. Wendling, C. Demougeot
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Rheumatoid Arthritis (RA) is associated to an increase in cardiovascular risk (CVR) explained in part by accelerated atherosclerosis as a consequence of endothelial dysfunction. Glucocorticoids (GCs) are widely prescribed in RA patients. Surprisingly, despite the commonly held belief that glucocorticoids worsen the CVR, data concerning their impact on endothelial function in RA is lacking. <h3>Objectives</h3> The present study investigated the effect of a high dose of prednisolone on vascular function in arthritic rats and identified the underlying mechanisms. <h3>Methods</h3> Adjuvant-induced arthritis (AIA) was induced in 6-week-old male Lewis rats by injection of <i>Mycobacterium butyricum</i> in adjuvant at the basis of the tail. At the onset of arthritis, rats were daily treated (i.p.) with prednisolone (10 mg /kg, AIA-GC) or saline (Vehicle) for 21 days. Arthritis score and tarsus diameter were daily monitored. At the end of treatment, thoracic aortas were harvested to measure the relaxation of pre-constricted aortic rings to acetylcholine in the presence or not of inhibitor of nitric oxide synthase (NOS) (L-NAME), arginase (nor-NOHA), COX-2 (NS-398), EDHF (Apamin/Charybdotoxin) or a superoxide dismutase analog (Tempol). The effect of a NO donor (sodium nitroprussiate, SNP) and norepineprhine (NE) was studied on endothelium-denuded aortic rings. Aortic expression of endothelial NOS (eNOS) and phospho-eNOS (Ser-1177) was evaluated by western blotting. Blood pressure, glycaemia, triglyceride and total cholesterol levels and radiological score of hind paws were also assessed. <h3>Results</h3> Consistent with the well-known effects of a high dose of GC, AIA-GC exhibited significantly higher blood pressure (p&lt;0.05) and triglyceride levels (p&lt;0.05) compared to AIA-vehicle (p&lt;0.05). Glycemia was unchanged and total cholesterol levels were lower (p&lt;0.01) in treated compared to untreated AIA. Arthritic scores, paw diameters and radiological damage were dramatically reduced by prednisolone (p&lt;0.001). In endothelium-denuded rings, vascular reactivity to SNP or to NE was unaffected by GC. By contrast, GC significantly improved endothelial function as attested by enhanced Ach-induced relaxation compared to AIA-vehicle. This beneficial effect relied on increased phosphorylation of NOS and a subsequent enhancement of NO synthase activity, increased EDHF production and decreased superoxide anions production and activity of arginase and COX-2. <h3>Conclusions</h3> Our study demonstrated that a high dose of prednisolone improved endothelial function in case of RA, independently of its deleterious cardio-metabolic effects. From a clinical perspective, these results raise the question of the use of high doses of GC during a short period to overcome CV risk along with a rapid disease control. Whether this beneficial vascular effect of GC depends on the reduction of disease activity or not deserves further investigations. <h3>Disclosure of Interest</h3> None declared