Etanercept improves endothelial function via pleiotropic effects in rat adjuvant-induced arthritis

Totoson, Perle; Maguin‐Gaté, Katy; Prigent‐Tessier, Anne; Monnier, Alice; Verhoeven, Frank; Marie, Christine; Wendling, Daniel; Demougeot, Céline

doi:10.1093/rheumatology/kew062

Cited by 26 publications

(22 citation statements)

References 43 publications

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“…Furthermore, in line with the current guidelines recommending an aggressive control of disease activity for CV risk reduction in RA, we reported a negative correlation between arthritis score and endothelial function. By contrast, no correlation was observed between ED and circulating pro-in ammatory cytokines levels, as previously observed in the AIA model after treatment with etanercept, methotrexate, non-steroidal anti-in ammatory drugs or glucocorticoids (37)(38)(39)(40). This suggests that improvement of ED consecutive to Tofacitinib was independent on changes in circulating levels of these cytokines.…”

Section: Discussionsupporting

confidence: 44%

Vascular and cerebral benefits of Tofacitinib in rheumatoid arthritis: evidence in rat adjuvant-induced arthritis

Totoson¹,

Quirié²,

Pedard³

et al. 2020

Preprint

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Background: To determine vascular and cerebral effects of Tofacitinib in the adjuvant-induced arthritis (AIA) model in rat.Methods: At the first signs of arthritis (day 10-12 post-immunization), Tofacitinib (10 mg/kg s.c., twice daily) or vehicle were administered for 3 weeks in AIA rats. A group of non AIA served as controls. Body weights and arthritis scores were daily monitored. Anhedonia was explored with the saccharin preference test at day 4 (preclinical), day 11 (early) and day 28 (acute arthritis) post-immunization. At the end of the treatment, aorta, brain and blood were collected for analysis of endothelial function using acetylcholine (Ach)-induced relaxation, brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus (Hip) and prefrontal cortex (PFC), and IL-1β, TNFα, IL-17A plasma levels. Radiographic score of paws was also assessed. Results: As compared to vehicle, Tofacitinib reduced body weight loss, arthritis and radiographic scores (p<0.001) but did not change plasma levels of pro-inflammatory cytokines. Tofacitinib fully prevented AIA-associated reduction in Ach-induced relaxation. As compared to controls, vehicle-treated AIA exhibited low BDNF levels in PFC (p<0.001) and anhedonia at all times examined (p<0.05). Tofacinib did not improve anhedonia, but resulted in elevation of BDNF levels both in PFC (p<0.05) and Hip (p<0.001). A positive correlation was observed between brain BDNF levels and endothelial function (p<0.05).Conclusion: Restoration of normal endothelial function and elevation of brain BDNF levels by Tofacitinib in AIA rats support a positive effect of this new antirheumatic drug on cardiovascular and neuropsychiatric comorbidities of rheumatoid arthritis.

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Section: Discussionsupporting

confidence: 44%

Vascular and cerebral benefits of Tofacitinib in rheumatoid arthritis: evidence in rat adjuvant-induced arthritis

Totoson¹,

Quirié²,

Pedard³

et al. 2020

Preprint

Self Cite

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“…To investigate whether the effects of GCs on endothelial function relied upon changes in protein expression, the protein content of eNOS and phospho-Ser1177-eNOS (P-eNOS, an activated form of eNOS at serine 1177 that produces a sustained release of endothelial NO), arginase-2, COX-2, p22 phox and p47 phox [membrane-bound and cytosolic components, respectively, of nicotinamide adenine dinucleotide phosphate (NADPH oxidase), a major vascular enzyme responsible for O -2 8 production], was assessed in homogenates of thoracic aortas from vehicle and GC groups by Western blotting analysis, as described previously in detail [25] (see Supporting information).…”

Section: Western Blot Analysismentioning

confidence: 99%

Glucocorticoids improve endothelial function in rheumatoid arthritis: a study in rats with adjuvant-induced arthritis

Verhoeven

Totoson

Maguin‐Gaté

et al. 2017

Clinical and Experimental Immunology

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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, p22 and p47 was 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.

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“…These data have to be replicated and confirmed, in particular using a monoclonal anti-rat TNF antibody rather than the soluble receptor construct etanercept, as contradictory data on the effects of etanercept in rats have been reported ( 46 – 49 ). Unfortunately, tools to block TNF in rats are limited.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Activation Can Trigger Experimental Spondyloarthritis in HLA-B27/Huβ2m Transgenic Rats

et al. 2017

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Spondyloarthritis (SpA) does not display the typical features of auto-immune disease. Despite the strong association with MHC class I, CD8+ T cells are not required for disease induction in the HLA-B27/Huβ2m transgenic rats. We used Lewis HLA-B27/Huβ2m transgenic rats [21-3 × 283-2]F1, HLA-B7/Huβ2m transgenic rats [120-4 × 283-2]F1, and wild-type rats to test our hypothesis that SpA may be primarily driven by the innate immune response. In vitro, splenocytes were stimulated with heat-inactivated Mycobacterium tuberculosis and cytokine expression and production was measured. In vivo, male and female rats were immunized with 30, 60, or 90 µg of heat-inactivated M. tuberculosis and clinically monitored for spondylitis and arthritis development. After validation of the model, we tested whether prophylactic and therapeutic TNF targeting affected spondylitis and arthritis. In vitro stimulation with heat-inactivated M. tuberculosis strongly induced gene expression of pro-inflammatory cytokines such as TNF, IL-6, IL-1α, and IL-1β, in the HLA-B27 transgenic rats compared with controls. In vivo immunization induced an increased spondylitis and arthritis incidence and an accelerated and synchronized onset of spondylitis and arthritis in HLA-B27 transgenic males and females. Moreover, immunization overcame the protective effect of orchiectomy. Prophylactic TNF targeting resulted in delayed spondylitis and arthritis development and reduced arthritis severity, whereas therapeutic TNF blockade did not affect spondylitis and arthritis severity. Collectively, these data indicate that innate immune activation plays a role in the initiation of HLA-B27-associated disease and allowed to establish a useful in vivo model to study the cellular and molecular mechanisms of disease initiation and progression.

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Etanercept improves endothelial function via pleiotropic effects in rat adjuvant-induced arthritis

Cited by 26 publications

References 43 publications

Vascular and cerebral benefits of Tofacitinib in rheumatoid arthritis: evidence in rat adjuvant-induced arthritis

Vascular and cerebral benefits of Tofacitinib in rheumatoid arthritis: evidence in rat adjuvant-induced arthritis

Glucocorticoids improve endothelial function in rheumatoid arthritis: a study in rats with adjuvant-induced arthritis

Innate Immune Activation Can Trigger Experimental Spondyloarthritis in HLA-B27/Huβ2m Transgenic Rats

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