Treatment with the arginase inhibitor Nw-hydroxy-nor-L-arginine restores endothelial function in rat adjuvant-induced arthritis
1 EA 4267 Fonctions et Dysfonctions epithéliales, University of Franche Comté, 19 rue Ambroise Paré, 25030 Besançon, France
2 Department of Rheumatology, University Hospital Jean Minjoz, 3 bd Fleming, 25000 Besançon, France
3 Department of Pathologic Anatomy, University Hospital Jean Minjoz, 3 bd Fleming, 25000 Besançon, France
4 EA 4266 Agents pathogènes et inflammation, University of Franche Comté, 2 place St Jacques, 2503 Besançon, France
Arthritis Research & Therapy 2012, 14:R130 doi:10.1186/ar3860Published: 30 May 2012
Endothelial dysfunction (ED) participates to atherogenesis associated to rheumatoid arthritis. We recently reported increased arginase activity/expression in vessels from adjuvant-induced arthritis (AIA) rats. In the present study, we investigated the effects of a curative treatment with the arginase inhibitor Nw-hydroxy-nor-L-arginine (nor-NOHA) on vascular dysfunction in AIA rats.
AIA rats were treated with nor-NOHA (40 mg/kg/d, ip) for 21 days after the onset of arthritis. A group of untreated AIA rats and a group of healthy rats served as controls. ED was assessed by the vasodilatory effect of acetylcholine (Ach) on aortic rings. The role of superoxide anions, prostanoids, endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide synthase (NOS) pathway was studied. Plasma levels of IL-6 and vascular endothelial growth factor (VEGF) were determined by ELISA kits. Arthritis severity was estimated by a clinical, radiological and histological analysis.
Nor-NOHA treatment fully restored the aortic response to Ach to that of healthy controls. The results showed that this beneficial effect is mediated by an increase in NOS activity and EDHF and reduced superoxide anion production as well as a decrease in the activity of cyclooxygenase (COX)-2, thromboxane and prostacyclins synthases. In addition, nor-NOHA decreased IL-6 and VEGF plasma levels in AIA rats. By contrast, the treatment did not modify arthritis severity in AIA rats.
The treatment with an arginase inhibitor has a potent effect on ED in AIA independently of the severity of the disease. Our results suggest that this new pharmacological approach has the potential as a novel add-on therapy in the treatment of RA.