Glucocorticoids improve endothelial function in rheumatoid arthritis: a study in rats with adjuvant-induced arthritis.
To determine the effect of glucocorticoids (GCs) on endothelial dysfunction (ED) and on traditional cardiovascular (CV) risk factors in the adjuvant-induced arthritis (AIA) rat model. At the first signs of AIA, a high dose (HD) [10 mg/kg/day, intraperitoneally (i.p.), GC-HD] or low dose (LD) (1 mg/kg/day, i.p., GC-LD) of prednisolone was administered for 3 weeks. Endothelial function was studied in aortic rings relaxed with acetylcholine (Ach) with or without inhibitors of nitric oxide synthase (NOS), cyclooxygenase 2 (COX-2), arginase, endothelium derived hyperpolarizing factor (EDHF) and superoxide anions ( O2-°) production. Aortic expression of endothelial NOS (eNOS), Ser1177-phospho-eNOS, COX-2, arginase-2, p22phoxand p47phoxwas evaluated by Western blotting analysis. Arthritis scores, blood pressure, heart rate and blood levels of cytokines, triglycerides, cholesterol and glucose were measured. GC-HD but not GC-LD reduced arthritis score significantly and improved Ach-induced relaxation (P < 0·05). The positive effect of GC-HD resulted from increased NOS activity and EDHF production and decreased COX-2/arginase activities and O2-° production. These functional effects relied upon increased phospho-eNOS expression and decreased COX-2, arginase-2 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression. Despite the lack of effect of GC-LD on ED, it increased NOS and EDHF and down-regulated O2-° pathways but did not change arginase and COX-2 pathways. GC-HD increased triglycerides levels and blood pressure significantly (P < 0·05). Both doses of GCs decreased to the same extent as plasma interleukin (IL)-1β and tumour necrosis factor (TNF)-α levels (P < 0·05). Our data demonstrated that subchronic treatment with prednisolone improved endothelial function in AIA via pleiotropic effects on endothelial pathways. These effects occurred independently of the deleterious cardiometabolic effects and the impact of prednisolone on systemic inflammation.
PEPITE EA4267, FHU INCREASE, Université Bourgogne Franche-Comté, Besançon, France.|Service de Rhumatologie, CHRU Besançon, France.
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F
Verhoeven
PEPITE EA4267, FHU INCREASE, Université Bourgogne Franche-Comté, Besançon, France.
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Totoson
PEPITE EA4267, FHU INCREASE, Université Bourgogne Franche-Comté, Besançon, France.
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K
Maguin-Gaté
INSERM U1093, Université Bourgogne Franche-Comté, Dijon, France.
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Prigent-Tessier
INSERM U1093, Université Bourgogne Franche-Comté, Dijon, France.
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Marie
Service de Rhumatologie, CHRU Besançon, France.|EA 4266, Université Bourgogne Franche-Comté, Besançon, France.
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Wendling
PEPITE EA4267, FHU INCREASE, Université Bourgogne Franche-Comté, Besançon, France.
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Moretto
PEPITE EA4267, FHU INCREASE, Université Bourgogne Franche-Comté, Besançon, France.|Service de Rhumatologie, CHRU Besançon, France.
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Prati
PEPITE EA4267, FHU INCREASE, Université Bourgogne Franche-Comté, Besançon, France.
C
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Demougeot
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D001119:Arginase / Q000494:pharmacology; D001168:Arthritis; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology; D001685:Biological Factors / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000175:diagnosis; D002784:Cholesterol / Q000097:blood; D051546:Cyclooxygenase 2 / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D005938:Glucocorticoids / Q000008:administration & dosage*; D006339:Heart Rate; D008297:Male; D011239:Prednisolone / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D013481:Superoxides / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D001685:Biological Factors; D001786:Blood Glucose; D016207:Cytokines; D005938:Glucocorticoids; D014280:Triglycerides; C067410:endothelium-dependent hyperpolarization factor; D013481:Superoxides; D002784:Cholesterol; D011239:Prednisolone; D051546:Cyclooxygenase 2; D001119:Arginase; D000109:Acetylcholine
adjuvant-induced arthritis; endothelial dysfunction; glucocorticoids; mechanisms