Vascular Arginase Is a Relevant Target to Improve Cerebrovascular Endothelial Dysfunction in Rheumatoid Arthritis: Evidence from the Model of Adjuvant-Induced Arthritis

Bordy, Romain; Quirié, Aurore; Marie, Christine; Wendling, Daniel; Totoson, Perle; Demougeot, Céline

doi:10.1007/s12975-019-00699-7

Cited by 10 publications

(6 citation statements)

References 44 publications

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“…AIA is a reliable model to investigate ED in RA. Indeed, ED in AIA was reported to affect conductance and resistance vessels either of the peripheral or cerebral circulation [5,31,33], as observed in RA patients [3,4,34]. Using this model, the present study demonstrated that Tofacitinib administered from the first signs of arthritis fully prevented ED.…”

Section: Discussionsupporting

confidence: 66%

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

Totoson

Peyronnel

Quirié

et al. 2021

Fundamemntal Clinical Pharma

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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 À 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. K E Y W O R D S arthritis, BDNF, peripheral endothelial dysfunction, Tofacitinib | INTRODUCTIONRheumatoid arthritis (RA), the most common systemic autoimmune disease, is characterized by a reduced life expectancy. Cardiovascular diseases (CVD), including myocardial infarction and stroke, are the main cause of premature mortality and sudden death in RA [1]. Evidence from clinical studies showed that endothelial dysfunction (ED), the "sine qua non" condition for atherosclerosis appearance, is the key promoter of CVD and as such is a seminal target for reducing cardiovascular (CV) risk in RA [2]. Clinical and preclinical studies indicated that ED affects the macrovasculature and microvasculature in RA, at the systemic and Perle Totoson and Celian Peyronnel contributed equally to this work.

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Section: Discussionsupporting

confidence: 66%

“…cerebral levels [3][4][5]. A combination of multiple factors in RA might contribute to ED including genetic factors, immune dysregulation, systemic inflammation, modifiable traditional CV risk factors (high blood pressure, dyslipidemia, diabetes, and smoking), sedentary behavior, and/or iatrogenic factors [4].…”

mentioning

confidence: 99%

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

Totoson

Peyronnel

Quirié

et al. 2021

Fundamemntal Clinical Pharma

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“…Finally, the precise role of endothelial BDNF in the brain remains speculative, but there is compelling evidence suggesting its involvement in cerebral vessel vasodilation ( Santhanam et al, 2010 ; Bordy et al, 2020 ), cerebral angiogenesis ( Kim et al, 2004 ) and neuroplastic processes ( Marie et al, 2018 ). The presence of endothelial TrkB-FL receptors suggests that endothelial BDNF may exert an autocrine effect by promoting NO production, which could then diffuse from endothelial cells to neurons, enhancing LTP and neuroplasticity ( Hopper and Garthwaite, 2006 ).…”

Section: Cerebral Mechanisms Involved In Ex-increased Bdnf Productionmentioning

confidence: 99%

Molecular mechanisms underlying physical exercise-induced brain BDNF overproduction

Cefis,

Chaney,

Wirtz

et al. 2023

Front. Mol. Neurosci.

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Accumulating evidence supports that physical exercise (EX) is the most effective non-pharmacological strategy to improve brain health. EX prevents cognitive decline associated with age and decreases the risk of developing neurodegenerative diseases and psychiatric disorders. These positive effects of EX can be attributed to an increase in neurogenesis and neuroplastic processes, leading to learning and memory improvement. At the molecular level, there is a solid consensus to involve the neurotrophin brain-derived neurotrophic factor (BDNF) as the crucial molecule for positive EX effects on the brain. However, even though EX incontestably leads to beneficial processes through BDNF expression, cellular sources and molecular mechanisms underlying EX-induced cerebral BDNF overproduction are still being elucidated. In this context, the present review offers a summary of the different molecular mechanisms involved in brain’s response to EX, with a specific focus on BDNF. It aims to provide a cohesive overview of the three main mechanisms leading to EX-induced brain BDNF production: the neuronal-dependent overexpression, the elevation of cerebral blood flow (hemodynamic hypothesis), and the exerkine signaling emanating from peripheral tissues (humoral response). By shedding light on these intricate pathways, this review seeks to contribute to the ongoing elucidation of the relationship between EX and cerebral BDNF expression, offering valuable insights into the potential therapeutic implications for brain health enhancement.

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“…Chronic inflammation is one the most critical mechanisms of endothelial dysfunction [4,8]. Patients with chronic inflammatory diseases, such as rheumatoid arthritis [28], inflammatory bowel diseases [29], lupus [30] and others, manifest endothelial dysfunction, often in the early phase of the disease. Increased inflammatory markers have been reported linked with decreased FMD and linked to a wide variety of major adverse cardiovascular events [8].…”

Section: Discussionmentioning

confidence: 99%

Circulating senescent angiogenic T cells are linked with endothelial dysfunction and systemic inflammation in hypertension

Zhang

Liu

Qiu

et al. 2020

Journal of Hypertension

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Objective: Angiogenic T cells (T ang cells), a recently discovered T-cell subset, have been reported involved in the repair of endothelial injury. The purpose of this study was to explore the correlation of immunologic senescence and pro-inflammatory capacity of T ang cells with endothelial dysfunction in hypertensive patients. Methods: Immunological characteristics of T ang cells (CD3 + CD31 + CXCR4 + ) from hypertensive patients with or without endothelial dysfunction were elucidated by surface immunophenotyping and intracellular cytokine staining. Endothelial function was measured by flow-mediated dilation (FMD). Results: The frequency of CD28 null subset in CD4 + T ang cells was notably elevated in hypertensive patients with endothelial dysfunction, which was negatively associated with FMD. The high frequency of CD28 null CD4 + T ang cells was an independent risk factor of endothelial dysfunction with good diagnostic performance in ROC curve analysis. Immunophenotyping revealed that this specific subset of T ang cells exhibited senescent profile and has low hTERT expression. CD28 null CD4 + T ang cells produced high levels of inflammatory cytokines, IL-6, IFN-γ and TNF-α, and significantly correlated with the systemic inflammation in hypertensive patients with endothelial dysfunction. Conclusion: Collectively, our findings demonstrate for the first time that CD28 null subset in CD4 + T ang cells with senescent and pro-inflammatory phenotype is dependently correlated with impaired FMD and systemic inflammation, which might contribute to the immunopathologic mechanism of endothelial dysfunction. Identification of a pathogenic CD4 + T ang -cell subset lacking CD28 may offer opportunities for the evaluation and management of endothelial dysfunction in hypertension.

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Vascular Arginase Is a Relevant Target to Improve Cerebrovascular Endothelial Dysfunction in Rheumatoid Arthritis: Evidence from the Model of Adjuvant-Induced Arthritis

Cited by 10 publications

References 44 publications

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

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

Molecular mechanisms underlying physical exercise-induced brain BDNF overproduction

Circulating senescent angiogenic T cells are linked with endothelial dysfunction and systemic inflammation in hypertension

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