Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Abstract

Objective. To investigate whether arginase pathway abnormalities occur in vessels from rats with adjuvant-induced arthritis (AIA), and to determine whether the up-regulation of arginase, which reciprocally regulates nitric oxide synthase (NOS) by competing for the same substrate, L-arginine, contributes to endothelial dysfunction in AIA.Methods. We performed vascular reactivity experiments on thoracic aortic rings from AIA rats and control rats, and we investigated the response of rings to norepinephrine (NE), sodium nitroprusside (SNP), and acetylcholine (ACh). ACh-induced relaxation was evaluated in the presence (or not in the presence) of the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME), the arginase inhibitor N -hydroxy-nor-Larginine (nor-NOHA), or both. Aortic arginase activity was measured using a spectrophotometric method, and the expression of arginase and endothelial NOS (eNOS) was evaluated by Western blotting.Results. ACh-induced vasodilation was significantly impaired in AIA rats, while the responses to NE and to SNP did not differ from those in control rats. L-NAME reduced ACh-induced vasodilation to a lesser extent in AIA rats than in control rats. Incubation of aortic rings with nor-NOHA enhanced the vascular response to ACh in AIA rats and reversed the effects of L-NAME. Compared with control rats, AIA rats exhibited increased vascular expression of arginase II (by 22%) (P < 0.05) as well as increased arginase activity (by 49%) (P < 0.05), whereas eNOS expression was unchanged. Finally, arginase activity and expression correlated positively with arthritis severity.Conclusion. Our results are consistent with the notion that arginase up-regulation plays a role in AIAassociated endothelial dysfunction. They suggest that arginase might be an attractive new target for treating endothelial dysfunction in arthritis.

Endothelial Dysfunction in an Ovine Model of Collagen-Induced Arthritis

“…This result provides evidence that coronary vascular smooth muscle function was unaffected, and therefore the functional deficit observed in response to bradykinin is due to specific dysfunction of endothelial cells. This finding is consistent with studies of rats with adjuvant-induced arthritis [7,8] and studies of humans with RA [5,46] which have reported no alteration in vascular smooth muscle function associated with arthritis.…”

“…Therefore, the endothelial dysfunction in this study would appear to be of a different form. The result is, however, consistent with findings in rodent models of arthritis and human RA patients, in which the response of endothelial cells to Gq-coupled agonists such as acetylcholine have been shown to be attenuated [3,7,8]. Although further studies of agonists coupled to Gi proteins would be required to confirm dysfunction of this G-protein type, our results suggest that the endothelial dysfunction induced in chronic inflammation is not restricted to either signalling pathway.…”

“…There are limited previous reports of endothelial dysfunction associated with arthritis in animal models. All currently reported studies have utilized the rat model of adjuvant-induced arthritis [7,8,30,31,32,38]. As such, this study represents the first report of endothelial dysfunction in a large animal model, and also the first in a collagen-induced arthritis model.…”

“…Endothelial dysfunction is a significant finding, as it has been linked to the development of clinical cardiovascular disease in the general population [6]. Endothelial dysfunction has also previously been described in rodent models of RA; however, the mechanisms leading to this dysfunction are still incompletely understood [7,8]. Experimentally induced systemic inflammatory responses induce endothelial dysfunction, and it is therefore likely that the severe inflammatory response associated with clinical RA is responsible for the development of vascular pathology [9,10].…”

“…Endothelial dysfunction has previously been described in rat adjuvant-induced arthritis [7,8,30,31,32]; however, it has not been described in any large animal model of arthritis. Large animal models of inflammatory disease have a number of advantages over rodent models, including important practical concerns such as more accurate monitoring and sampling.…”