Treatment with the arginase inhibitor Nw-hydroxy-nor-L-arginine restores endothelial function in rat adjuvant-induced arthritis.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
EA 4267 Fonctions et Dysfonctions epithéliales, University of Franche Comté, 19 rue Ambroise Paré, 25030 Besançon, France. praticlement@gmail.com
Clément
C
Prati
Alain
A
Berthelot
Bernadette
B
Kantelip
Daniel
D
Wendling
Céline
C
Demougeot
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001119:Arginase / Q000037:antagonists & inhibitors; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D015850:Interleukin-6; C404735:N(omega)-hydroxynorarginine; D042461:Vascular Endothelial Growth Factor A; D001120:Arginine; D001119:Arginase