Effect of Nabumetone Treatment on Vascular Responses of the Thoracic Aorta in Rat Experimental Arthritis

Ülker, Sibel; Önal, Aytül; Hatip, Funda Bölükbaşı; Sürücü, Ayşe; Alkanat, Murat; Koşay, Sezen; Evinç, Akgün

doi:10.1159/000028358

Cited by 20 publications

(17 citation statements)

References 13 publications

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“…In the present study, we investigated endothelial function in the AIA model, which is commonly accepted as having many histologic and clinical features in common with human RA (31) and which is widely used to predict clinical efficacy of new therapies in RA (32). In accordance with previous studies (12)(13)(14)(15)(16)(33)(34)(35), our data show that endothelial function assessed by the vasodilating response to ACh is impaired in AIA rats. We also demonstrated that endothelial dysfunction correlates with disease activity.…”

Section: Discussionsupporting

confidence: 79%

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

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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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.

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Section: Discussionsupporting

confidence: 79%

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

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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“…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.…”

Section: Discussionmentioning

confidence: 91%

Endothelial Dysfunction in an Ovine Model of Collagen-Induced Arthritis

Dooley

Washington²,

Abdalmula³

et al. 2014

J Vasc Res

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Background: Rheumatoid arthritis (RA) induces systemic inflammation, producing a range of co-morbidities including cardiovascular disease. An early vascular change is endothelial dysfunction, characterized by reduced endothelium-dependent vasodilation. The aim of this study was to assess endothelial function in isolated coronary and digital arteries using an ovine model of collagen-induced RA. Methods: Sheep were culled following induction of arthritis, and their endothelial function was compared to that of normal sheep. Paired arterial segments were mounted in a wire myograph and dilated with endothelium-dependent vasodilators [bradykinin, serotonin, carbachol and adenosine diphosphate (ADP); linked to either Gi or Gq signalling pathways] and endothelium-independent dilators (adenosine and sodium nitroprusside) to construct cumulative concentration-response curves. Results: Coronary arteries from arthritic sheep exhibited a significantly greater EC₅₀ value for bradykinin-induced relaxation compared to non-arthritic controls (2.9 × 10^-8M for arthritic sheep vs. 8.6 × 10^-9M for controls). Digital arteries from arthritic sheep also exhibited a significantly greater EC₅₀ for relaxation to ADP and a significant decrease in the carbachol maximal response. Responses to sodium nitroprusside were unchanged in both coronary and digital arteries. Conclusion: Sheep with RA demonstrated attenuated arterial relaxation to endothelium-dependent vasodilators. This may provide a useful model of endothelial dysfunction in chronic inflammatory conditions. The dysfunction did not appear to be associated with one specific G-protein signalling pathway.

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“…It is noteworthy that the ED severity mirrors the arthritis severity. Indeed, at day 24 post-injection in AIA, no alteration of ACh-induced relaxation was found in grade 1 arthritic rats whereas rats with grade 2 or 3 arthritis exhibited a reduced relaxation to ACh [16]. Likewise, at day 35 post-injection, we identified an inverse correlation between the maximal effect of ACh and the arthritis grade [22].…”

Section: Endothelial Dysfunction In Animal Models Of Arthritismentioning

confidence: 99%

Mechanisms of endothelial dysfunction in rheumatoid arthritis: lessons from animal studies

Totoson¹,

Maguin‐Gaté²,

Prati

et al. 2014

Arthritis Res Ther

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Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by articular and extra-articular manifestations involving cardiovascular diseases (CVDs), which account for 30% to 50% of all deaths. In patients with RA, atherosclerosis lesions occur earlier and have a more rapid evolution than in the general population. Beyond mortality, the impact of CVD on quality of life, combined with the associated increase in health-care costs, renders CVD in RA a major public health problem. Recent studies showed that patients with RA are characterized by the presence of endothelial dysfunction (ED), which is recognized as a key event in the development of atherosclerosis. By definition, ED is a functional and reversible alteration of endothelial cells, leading to a shift of the actions of the endothelium toward reduced vasodilation, proinflammatory state and proliferative and prothrombotic properties. Although the improvement of endothelial function is becoming an important element of the global management of patients with RA, the mechanistic determinants of ED in RA are still poorly understood. Animal models of RA provide the unique opportunity to unravel the pathophysiological features of ED in RA. The present review summarizes the available data on mechanisms underlying ED in animal models of RA and proposes attractive prospects in order to discover novel therapeutic strategies of RA-associated ED.

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Effect of Nabumetone Treatment on Vascular Responses of the Thoracic Aorta in Rat Experimental Arthritis

Cited by 20 publications

References 13 publications

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

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

Endothelial Dysfunction in an Ovine Model of Collagen-Induced Arthritis

Mechanisms of endothelial dysfunction in rheumatoid arthritis: lessons from animal studies

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