Endothelial Dysfunction in Rheumatoid Arthritis: Mechanistic Insights and Correlation with Circulating Markers of Systemic Inflammation

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Effects of a chronic l -arginine supplementation on the arginase pathway in aged rats

International audienceWhile ageing is frequently associated with l-arginine deficiency, clinical and experimental studies provided controversial data on the interest of a chronic l-arginine supplementation with beneficial, no or even deleterious effects. It was hypothesized that these discrepancies might relate to a deviation of l-arginine metabolism towards production of l-ornithine rather than nitric oxide as a result of age-induced increase in arginase activity. This study investigated the effect of ageing on arginase activity/expression in target tissues and determined whether l-arginine supplementation modulated the effect of ageing on arginase activity. Arginase activity and expression were measured in the heart, vessel, brain, lung, kidney and liver in young rats (3-months old) and aged Wistar rats (22–24-months-old) with or without l-arginine supplementation (2.25% in drinking water for 6 weeks). Plasma levels of l-arginine and l-ornithine were quantified in order to calculate the plasma l-arginine/l-ornithine ratio, considered as a reflection of arginase activity. Cardiovascular parameters (blood pressure, heart rate) and aortic vascular reactivity were also studied. Ageing dramatically reduced plasma l-arginine and l-arginine/l-ornithine ratio, decreased liver and kidney arginase activities but did not change activities in other tissues. l-Arginine supplementation normalized plasma l-arginine and l-arginine/l-ornithine ratio, improved endothelial function and decreased systolic blood pressure. These effects were associated with decreased arginase activity in aorta along with no change in the other tissues except in the lung in which activity was increased. A strong mismatch was therefore observed between arginase activity and expression in analyzed tissues. The present study reveals that ageing selectively changes arginase activity in clearance tissues, but does not support a role of the arginase pathway in the potential deleterious effect of the l-arginine supplementation in aged patients. Moreover, our data argue against the use of the measurement of plasma l-arginine/l-ornithine ratio to estimate arginase activity in aged patients

Diclofenac but not celecoxib improves endothelial function in rheumatoid arthritis: A study in adjuvant-induced arthritis

International audienceBackground and aims: We aimed at investigating the effect of celecoxib (COX-2 selective inhibitor) and diclofenac (non-selective COX inhibitor) on endothelial function, and at identifying the underlying mechanisms in adjuvant-induced arthritis (AIA).Methods: At the first signs of AIA, diclofenac (5 mg/kg twice a day, i.p), celecoxib (3 mg/kg/day, i.p) or saline (Vehicle) was administered for 3 weeks. Endothelial function was studied in aortic rings relaxed with acetylcholine (Ach) with or without inhibitors of NOS, arginase, EDHF and superoxide anions (O-2(-degrees)) production. Aortic expression of eNOS, Ser1177-phospho-eNOS, COX-2, arginase-2, p22(phox) and p47(phox) was evaluated by Western blotting analysis. Arthritis scores, blood pressure, glycaemia and serum ADMA levels were measured.Results: Diclofenac and celecoxib significantly reduced arthritis score to the same extent (p<0.05). As compared to vehicle-treated AIA, celecoxib did not change whereas diclofenac improved endothelial function (p<0.05) through increased EDHF production, decreased arginase activity and expression, decreased superoxide anions production and expression of p22(phox) and p47(phox). Diclofenac but not celecoxib significantly enhanced blood pressure and serum ADMA levels. Glycaemia was unchanged by both treatments.Conclusions: Our study reveals that the effect of NSAIDs on endothelial function cannot be extrapolated from their impact on arthritis severity and suggest that changes in blood pressure and plasma ADMA levels may not be useful to predict CV risk of NSAIDs in RA. (C) 2017 Elsevier B.V. All rights reserved

Investigation of Mammal Arginase Inhibitory Properties of Natural Ubiquitous Polyphenols by Using an Optimized Colorimetric Microplate Assay

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Effects of isometric strength training followed by no exercise and Humulus lupulus L-enriched diet on bone metabolism in old female rats

International audienceWe investigated in female rats the effects on bone metabolism of a prolonged no-training period, subsequent to an isometric exercise program, performed during young adulthood and those of a long-term consumption of Humulus lupulus L-enriched diet (genistein 1.92 and daidzein 1.24 mg/kg diet) combined or not with isometric training. Forty-eight rats (4 weeks old) were randomly divided into 4 groups: trained (C-Tr) or nontrained rats (C-NTr) fed with control diet and trained (H-Tr) or nontrained rats (H-NTr) fed with Humulus lupulus L-enriched diet. The diets lasted 100 weeks. Training was followed over a 25-week period. Bone parameters were measured at week 100. Our results showed that no significant difference was observed among the 4 groups in uterine relative weight, calcium (Ca) intake, fecal Ca, urinary Ca excretion, net Ca absorption, plasma Ca, and bone Ca content. Calcium balance was significantly enhanced in H-NTr rats in comparison with C-NTr and C-Tr rats. Isometric strength training led to a significant increase in total bone mineral density (BNID), diaphyseal BMD, and osteocalcin-deoxypyridinoline ratio in C-Tr rats compared with the other groups. The main findings of the present study indicate that in female rats, a 25-week isometric strength training performed during young adulthood followed by a prolonged no-training period increases BNID values and osteocalcin-deoxypyridinoline ratio, whereas long-term consumption of Humuluss lupulus L-enriched diet does not improve bone parameters. It suggests that bone gains induced by exercise do not decrease immediately after cessation of training and also confirms the importance of the practice of physical activity during puberty and young adulthood to maximize the achieved peak bone density

Treatment with an extract of Terminalia superba Engler & Diels decreases blood pressure and improves endothelial function in spontaneously hypertensive rats

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Tofacitinib improved peripheral endothelial dysfunction and brain‐derived neurotrophic factor levels in the rat adjuvant‐induced arthritis model

International audienceAbstract This study aimed to explore the effect of Tofacitinib on endothelial dysfunction and cerebral levels of brain‐derived neurotrophic factor (BDNF) in the adjuvant‐induced arthritis (AIA) rat model. Tofacitinib (10 mg/kg twice a day) or vehicle was administered from the first signs of inflammation. Arthritis scores were daily monitored while other parameters including endothelial function assessed from aortic rings, radiographic scores, blood pressure, heart rate, circulating levels of triglycerides, cholesterol, and interleukin (IL)‐1β, tumor necrosis factor‐α (TNF‐α), IL‐17A, and cerebral BDNF levels were determined after 3 weeks of treatment. A group of non‐AIA rats served as controls. In AIA rats, as compared with vehicle, Tofacitinib significantly reduced arthritis and radiographic scores, decreased total cholesterol and low‐density lipoprotein cholesterol (LDL‐C), but changed neither blood pressure nor heart rate and proinflammatory cytokines levels. It also fully restored acetylcholine (Ach)‐induced relaxation ( p < 0.05) through increased nitric oxide (NO) synthase activity, reduced BH 4 deficiency and O 2 −° production, decreased cyclo‐oxygenase‐2 (COX‐2)/arginase activities, and enhanced endothelium‐derived hyperpolarizing factor (EDHF) production. These effects translated into a decrease in atherogenic index and an elevation of BDNF levels in the prefrontal cortex ( p < 0.05) and hippocampus ( p < 0.001). The present study identified Tofacitinib as an efficient therapeutic option to reduce cardiovascular risk and improve BDNF‐dependent cognition in arthritis

Increased gut permeability and intestinal inflammation precede arthritis onset in the adjuvant-induced model of arthritis

Abstract Background Intestinal inflammation, dysbiosis, intestinal permeability (IP), and bacterial translocation (BT) have been identified in patients with spondyloarthritis but the time at which they appear and their contribution to the pathogenesis of the disease is still a matter of debate. Objectives To study the time-course of intestinal inflammation (I-Inf), IP, microbiota modification BT in a rat model of reactive arthritis, the adjuvant-induced arthritis model (AIA). Methods Analysis was performed at 3 phases of arthritis in control and AIA rats: preclinical phase (day 4), onset phase (day 11), and acute phase (day 28). IP was assessed by measuring levels of zonulin and ileal mRNA expression of zonulin. I-inf was assessed by lymphocyte count from rat ileum and by measuring ileal mRNA expression of proinflammatory cytokines. The integrity of the intestinal barrier was evaluated by levels of iFABP. BT and gut microbiota were assessed by LPS, soluble CD14 levels, and 16S RNA sequencing in mesenteric lymph node and by 16S rRNA sequencing in stool, respectively. Results Plasma zonulin levels increased at the preclinical and onset phase in the AIA group. Plasma levels of iFABP were increased in AIA rats at all stages of the arthritis course. The preclinical phase was characterized by a transient dysbiosis and increased mRNA ileal expression of IL-8, IL-33, and IL-17. At the onset phase, TNF-α, IL-23p19, and IL-8 mRNA expression were increased. No changes in cytokines mRNA expression were observed at the acute phase. Increased CD4 + and CD8 + T cell number was measured in the AIA ileum at day 4 and day 11. No increase in BT was observed. Conclusion These data show that intestinal changes precede the development of arthritis but argue against a strict “correlative” model in which arthritis and gut changes are inseparable