Anti‐inflammatory therapy for atherosclerosis: interpreting divergent results from the <scp>CANTOS</scp> and <scp>CIRT</scp> clinical trials

Ridker, Paul M.

doi:10.1111/joim.12862

Cited by 39 publications

(38 citation statements)

References 57 publications

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“…Strategies to lower CXCL10 expression can lead to reduced plaque formation and increased plaque stability (Segers et al, 2011). As previously described, it is possible that these increases correlate with IL-1β signaling pathways (Brown et al, 2015; Dinarello, 2010; Libby and Hansson, 2015; Ridker, 2013, 2019). However, the mechanisms through which Panx1 regulates these cytokines and chemokines remain to be fully elucidated.…”

Section: Discussionmentioning

confidence: 80%

“…Based on this, we focused on mechanisms controlling IL-1β, since directly targeting IL-1β is linked with a reduction in patient risk (Ridker et al, 2017). Critically, understanding the molecular mechanisms controlling IL-1β expression may provide avenues for future therapeutic intervention (Brown et al, 2015; Dinarello, 2010; Libby and Hansson, 2015; Ridker, 2013, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…Recent clinical trials have demonstrated that inflammation plays a key role in atherosclerotic disease development and that targeting specific cytokines may provide therapeutic benefits in high risk patients (Everett et al, 2013; Ridker, 2013, 2019; Ridker et al, 2019; Ridker et al, 2017; Ridker et al, 2012). In particular, the CANTOS trial demonstrated that the canakinumab, an anti-IL-1β therapeutic, reduces circulating levels of IL-1β in patients and decreases major adverse coronary events.…”

Section: Discussionmentioning

confidence: 99%

“…However, targeting pathways associated with IL-6 expression using low-dose methotrexate, did not result in significant patient benefits (Chan and Cronstein, 2010; Cronstein et al, 1993; Ridker et al, 2019). This has led to the suggestion that atherosclerosis may be under the control of IL-1β and that targeting pathways controlling or controlled by IL-1β may have therapeutic benefit (Brown et al, 2015; Dinarello, 2010; Libby and Hansson, 2015; Ridker, 2013, 2019). Here we show that TNF treatment of HUVEC cells leads to release of cytokines including IL-1β, which was significantly reduced when Panx1 expression was knocked down via siRNA.…”

Section: Discussionmentioning

confidence: 99%

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Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Yang

DeLalio

Best

et al. 2019

Preprint

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25inflammation, endothelial cell, smooth muscle cell 4 to prolonged tumor necrosis factor alpha (TNF) treatment, Yang et al. found that the Panx1 5 channel is targeted to the plasma membrane, where it facilitates an increase in intracellular 6 calcium to control the production and release of cytokines including IL-1β. 7 8 GRAPHICAL ABSTRACT 9 10 Graphical Abstract: The inflammatory process in endothelial cells is controlled by Ca 2+ entry through Pannexin 1 membrane channels. 3 Abstract 1The proinflammatory cytokine IL-1β is a significant risk factor in cardiovascular disease 2 that can be targeted to reduce major cardiovascular events. IL-1β expression and release 3 are tightly controlled by changes in intracellular Ca 2+ . In addition, purinergic signaling 4 through ATP release has also been reported to promote IL-1β production. Despite this, 5 the mechanisms that control IL-1β synthesis and expression have not been identified. 6The pannexin 1 (Panx1) channel has canonically been implicated in ATP release, 7 especially during inflammation. However, resolution of purinergic signaling occurs quickly 8 due to blood flow and the presence of ectonucleotidases. We examined Panx1 in human 9 endothelial cells following treatment with the pro-inflammatory cytokine tumor necrosis 10 alpha (TNF). In response to long-term TNF treatment, we identified a dramatic increase 11 in Panx1 protein expression at the plasma membrane. Analysis by whole transcriptome 12 sequencing (RNA-seq), qPCR, and treatment with specific kinase inhibitors, revealed that 13 TNF signaling induced NFκβ-associated Panx1 transcription. Genetic inhibition of Panx1 14 reduced the expression and secretion of IL-1β. We initially hypothesized that increased 15Panx1-mediated ATP release acted in a paracrine fashion to control cytokine expression. 16However, our data demonstrate that IL1-β expression was not altered after direct ATP 17 stimulation, following degradation of ATP by apyrase, or after pharmacological blockade 18 of P2 receptors. These data suggest that non-purinergic pathways, involving Panx1, 19 control IL-1β production. Because Panx1 forms a large pore channel, we hypothesized it 20 may act to passively diffuse Ca 2+ into the cell upon opening to regulate IL-1β. High-21 throughput flow cytometric analysis demonstrated that TNF treatments lead to elevated 22 intracellular Ca 2+ . Genetic or pharmacological inhibition of Panx1 reduced TNF-23 associated increases in intracellular Ca 2+ , and IL-1β transcription. Furthermore, we found 24 that the Ca 2+ -sensitive NFκβ-p65 protein failed to localize to the nucleus after genetic or 25 pharmacological block of Panx1. Taken together, our study provides the first evidence 26 that intracellular Ca 2+ regulation via the Panx1 channel induces a feed-forward effect on 27NFκβ to regulate IL-1β synthesis and release in endothelium during inflammation. 28 4 (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates

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Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Yang

DeLalio

Best

et al. 2019

Preprint

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“…As a consequence, anti‐inflammatory therapies may find clinical indications in this context. Paul M. Ridker, a pioneer in this field, compares the CANTOS (IL‐1β inhibition by use of a monoclonal antibody) and CIRT clinical trials (low‐dose methotrexate) in reducing athersosclerotic disease . Interestingly, whilst inhibition of inflammation using antibodies against IL‐1β reduced cardiovascular events, this was not apparent using low‐dose methotrexate in the CIRT trial.…”

mentioning

confidence: 99%

Innate immunity – a clinical perspective

2019

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Future of preventing and managing common chronic inflammatory diseases

Kornman

2020

Journal of Periodontology

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Chronic inflammation has emerged as a key factor that contributes to some common chronic diseases and reduces lifespan. Studies have identified multiple types of chronic inflammation ranging from autoimmune disease, which attacks specific tissues, to autoinflammatory diseases, which cause low-grade systemic inflammation and contribute to several common chronic diseases. This article highlights new perspectives on the role of chronic inflammation in cardiovascular disease (CVD). Such information is being leveraged to develop new treatment strategies for CVD and may inform how periodontal disease influences CVD.

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Anti‐inflammatory therapy for atherosclerosis: interpreting divergent results from the CANTOS and CIRT clinical trials

Abstract: Content List ‐ 15th Key symposium ‐ “Innate immunity”.

Cited by 39 publications

References 57 publications

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Innate immunity – a clinical perspective

Future of preventing and managing common chronic inflammatory diseases

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