Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis

Pérez-Baos, Sandra; Barrasa, Juan I.; Gratal, Paula; Larrañaga-Vera, A.; Prieto-Potín, Iván; Herrero‐Beaumont, Gabriel; Largo, Raquel

doi:10.1111/bph.13932

Cited by 42 publications

(36 citation statements)

References 68 publications

(84 reference statements)

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“…In agreement with this observation, in vitro experiments and in vivo animal models revealed that tofacitinib up-regulated ABCA1 expression, promoted anti-inflammatory macrophage polarization, improved EC function, and attenuated atherosclerosis (Table 1 and Fig. 3;De Vries et al, 2019;Furumoto et al, 2017;Pérez-Baos et al, 2017;Wang et al, 2017). However, recently the Oral Surveillance study revealed a statistically significant and clinically relevant increase in pulmonary embolism and an increased mortality in patients older than 50 yr with an increased CV risk when treated with a tofacitinib dose of 10 mg twice daily ( Fig.…”

Section: Anti-ifn/ifnar Signaling Therapiessupporting

confidence: 76%

Type-I interferons in atherosclerosis

Chen

Tas

Winther

2019

Journal of Experimental Medicine

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The contribution of dyslipidemia and inflammation in atherosclerosis is well established. Along with effective lipid-lowering treatments, the recent success of clinical trials with anti-inflammatory therapies and the accelerated atherosclerosis in many autoimmune diseases suggest that targeting inflammation may open new avenues for the prevention and the treatment for cardiovascular diseases (CVDs). In the past decades, studies have widened the role of type-I interferons (IFNs) in disease, from antivirus defense to autoimmune responses and immuno-metabolic syndromes. While elevated type-I IFN level in serum is associated with CVD incidence in patients with interferonopathies, experimental data have attested that type-I IFNs affect plaque-residing macrophages, potentiate foam cell and extracellular trap formation, induce endothelial dysfunction, alter the phenotypes of dendritic cells and T and B lymphocytes, and lead to exacerbated atherosclerosis outcomes. In this review, we discuss the production and the effects of type-I IFNs in different atherosclerosis-associated cell types from molecular biology studies, animal models, and clinical observations, and the potential of new therapies against type-I IFN signaling for atherosclerosis.

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Section: Anti-ifn/ifnar Signaling Therapiessupporting

confidence: 76%

Type-I interferons in atherosclerosis

Chen

Tas

Winther

2019

Journal of Experimental Medicine

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“…RNA was isolated according to manufacturer's protocol and cDNA was synthesized using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, USA). TaqMan Gene expression assays were used to quantify mRNA expression in StepOnePlus™ detection system using StepOne™ software v2.2 (Applied Biosystems) ( 19 , 34 ). HPRT was used as endogenous control and data was presented as relative expression to IL-1β and TNFα-stimulated chondrocytes or to healthy rabbits.…”

Section: Methodsmentioning

confidence: 99%

“…Human LDL were isolated from fresh plasma by sequential ultracentrifugation (34). After removing VLDL and IDL at 1.019 g/ml, LDL fraction between 1.019 and 1.063 g/ml was collected.…”

Section: Ldl Isolation and Cell Treatmentmentioning

confidence: 99%

Modulation of the Inflammatory Process by Hypercholesterolemia in Osteoarthritis

et al. 2020

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Objective: Several studies have linked metabolic syndrome to the development of osteoarthritis (OA) through hypercholesterolemia, one of its components. However, epidemiological studies showed contradictory results, and it is not clear how hypercholesterolemia itself, or oxidized LDL (oxLDL)-a pathological molecule potentially involved in this relationship-could be affecting OA. The objectives of this study were to investigate the effect of hypercholesterolemia induced by high-fat diet (HFD) in cartilage from OA rabbits, and how oxLDL affect human chondrocyte inflammatory and catabolic responses. Design: New Zealand rabbits were fed with HFD for 18 weeks. On week 6, OA was surgically induced. At the end of the study, cartilage damage and IL-1β, IL-6, MCP-1, MMP-13, and COX-2 expression in articular cartilage were evaluated. In addition, cultured human OA articular chondrocytes were treated with oxLDL at concentrations equivalent to those expected in synovial fluid from HFD rabbits, in the presence of IL-1β and TNFα. The effect of oxLDL on cell viability, nitric oxide production and catabolic and pro-inflammatory gene expression was evaluated. Results: HFD intake did not modify cartilage structure or pro-inflammatory and catabolic gene expression and protein presence, both in healthy and OA animals. OxLDL did not affect human chondrocyte viability, ADAMTS5 and liver X receptor (LXR) α gene expression, but decreased the induction of IL-1β, IL-6, MCP-1, MMP-13, iNOS, and COX-2 gene expression and MMP-13 and COX-2 protein presence, evoked by cytokines. Conclusions: Our data suggest that cholesterol intake per se may not be deleterious for articular cartilage. Instead, cholesterol de novo synthesis and altered cholesterol metabolism could be involved in the associations observed in human disease.

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“…The study also confirmed the role IFN-γ in formation of foam cells, representing the key element for development of atherosclerosis. Inhibition of JAK/STAT pathway by tofacitinib contributed to lipid release via enhanced expression of cellular liver X receptor α and ATP-binding cassette transporter (ABCA1) synthesis [ 83 ]. Similarities in mechanisms of action in those two studies may suggest the role of IL-6 as a mediator of changes in lipid metabolism.…”

Section: Safety Issues Of Jak Inhibitorsmentioning

confidence: 99%

Clinical Aspects of Janus Kinase (JAK) Inhibitors in the Cardiovascular System in Patients with Rheumatoid Arthritis

Kotyla

Islam

Engelmann

2020

IJMS

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Janus kinase (JAK) inhibitors, a novel class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs), have shown their safety and efficacy in rheumatoid arthritis (RA) and are being intensively tested in other autoimmune and inflammatory disorders. Targeting several cytokines with a single small compound leads to blocking the physiological response of hundreds of genes, thereby providing the background to stabilize the immune response. Unfortunately, blocking many cytokines with a single drug may also bring some negative consequences. In this review, we focused on the activity of JAK inhibitors in the cardiovascular system of patients with RA. Special emphasis was put on the modification of heart performance, progression of atherosclerosis, lipid profile disturbance, and risk of thromboembolic complications. We also discussed potential pathophysiological mechanisms that may be responsible for such JAK inhibitor-associated side effects.

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Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis

Abstract: Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients.

Cited by 42 publications

References 68 publications

Type-I interferons in atherosclerosis

Type-I interferons in atherosclerosis

Modulation of the Inflammatory Process by Hypercholesterolemia in Osteoarthritis

Clinical Aspects of Janus Kinase (JAK) Inhibitors in the Cardiovascular System in Patients with Rheumatoid Arthritis

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