Disturbed Blood Flow Induces RelA Expression via c-Jun N-Terminal Kinase 1

Simon, Chantal; Heiden, Kim Van der; Saliba, David; Tremoleda, Jordi L.; Khalil, Magdy M.; Zakkar, Mustafa; Chaudhury, Hera; Luong, Le Anh; Mason, Justin C.; Udalova, Irina A.; Gsell, William; Jones, Hazel A.; Haskard, Dorian O.; Krams, Rob; Evans, Paul C.

doi:10.1161/circresaha.110.233841

Cited by 104 publications

(56 citation statements)

References 51 publications

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“…The mechanism may involve eNOS, which was induced by ivabradine in our study and is known to inhibit inflammation via NO-dependent nitrosylation of pro-inflammatory signalling intermediaries and transcription factors 21,37 . Notably, previous studies revealed that high WSS enhanced the expression of eNOS and reduced VCAM-1 [18][19][20][21] . Thus we hypothesize that ivabradine suppresses EC expression of VCAM-1 via WSS-dependent induction of eNOS.…”

Section: Discussionmentioning

confidence: 99%

“…Animals were killed using pentobarbital (800 mg/kg by intraperitoneal injection). Endothelial expression of VCAM-1 or eNOS was determined by en face staining of the murine aorta as described 18,20 . Briefly, aortae were perfusion fixed and isolated prior to permeabilisation using 0.5% Triton X-100 (Sigma-Aldrich), and blocking with 20% goat serum for 2 h at room temperature.…”

Section: Animals Surgery Ivabradine Treatment and Dietmentioning

confidence: 99%

“…The levels of transcripts were assessed using quantitative real time PCR (qRT-PCR) as described 18,23 using gene-specific primers (Supplementary Table 1). Relative gene expression was calculated by comparing the number of thermal cycles that were necessary to generate threshold amounts of product.…”

Section: Animals Surgery Ivabradine Treatment and Dietmentioning

confidence: 99%

“…Low WSS promotes atherosclerosis by inducing endothelial expression of inflammatory molecules (e.g. VCAM-1) that promote lesions [18][19][20] , whereas high unidirectional WSS induces anti-inflammatory genes such as eNOS 21 . Although ivabradine is known to increase stroke volume and coronary perfusion 22 , its effects on WSS have not been studied.…”

Section: Introductionmentioning

confidence: 99%

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Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Luong¹,

Duckles²,

Schenkel³

et al. 2016

Thromb Haemost

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"Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries", Thrombosis and Haemostasis, 2016: 116/1 (July) pp. [181][182][183][184][185][186][187][188][189][190]., is available online at: https://doi.org/10.1160/TH16-03-0214.eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. 2 SUMMARY AimsBlood flow generates wall shear stress (WSS) which alters endothelial cell (EC) function. Low WSS promotes vascular inflammation and atherosclerosis whereas high uniform WSS is protective. Ivabradine decreases heart rate leading to altered hemodynamics. Besides its cardio-protective effects, ivabradine protects arteries from inflammation and atherosclerosis via unknown mechanisms. We hypothesised that ivabradine protects arteries by increasing WSS to reduce vascular inflammation. Methods and ResultsHypercholesterolemic mice were treated with ivabradine for 7 weeks in drinking water or remained untreated as a control. En face immunostaining demonstrated that treatment with ivabradine reduced the expression of pro-inflammatory VCAM-1 (p<0.01) and enhanced the expression of anti-inflammatory eNOS (p<0.01) at the inner curvature of the aorta. We concluded that ivabradine alters EC physiology indirectly via modulation of flow because treatment with ivabradine had no effect in ligated carotid arteries in vivo, and did not influence the basal or TNF -induced expression of inflammatory (VCAM-1, MCP-1) or protective (eNOS, HMOX1, KLF2, KLF4) genes in cultured EC. We therefore considered whether ivabradine can alter WSS which is a regulator of EC inflammatory activation. Computational fluid dynamics demonstrated that ivabradine treatment reduced heart rate by 20% and enhanced WSS in the aorta. ConclusionsIvabradine treatment altered hemodynamics in the murine aorta by increasing the magnitude of shear stress. This was accompanied by induction of eNOS and suppression of VCAM-1, whereas ivabradine did not alter EC that could not respond to flow. Thus ivabradine protects arteries by altering local mechanical conditions to trigger an anti-inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Section: Animals Surgery Ivabradine Treatment and Dietmentioning

confidence: 99%

Section: Animals Surgery Ivabradine Treatment and Dietmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Luong¹,

Duckles²,

Schenkel³

et al. 2016

Thromb Haemost

Self Cite

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“…This event then leads to the release of NF-κB heterodimers, which then translocate to the nucleus via importin proteins and drive a wide range of gene expression by binding to various κB elements. In the vascular endothelium, activation of NF-κB leads to the expression of proinflammatory genes, including those encoding cytokines, adhesion molecules, and chemoattractant proteins that together play critical roles in all aspects of the inflammatory and immune responses (21)(22)(23)(24)(25)(26). Thus, targeting NF-κB-mediated EC activation holds promise for the development of novel antiinflammatory therapies.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-181b regulates NF-κB–mediated vascular inflammation

et al. 2012

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EC activation and dysfunction have been linked to a variety of vascular inflammatory disease states. The function of microRNAs (miRNAs) in vascular EC activation and inflammation remains poorly understood. Herein, we report that microRNA-181b (miR-181b) serves as a potent regulator of downstream NF-κB signaling in the vascular endothelium by targeting importin-α3, a protein that is required for nuclear translocation of NF-κB. Overexpression of miR-181b inhibited importin-α3 expression and an enriched set of NF-κB-responsive genes such as adhesion molecules VCAM-1 and E-selectin in ECs in vitro and in vivo. In addition, treatment of mice with proinflammatory stimuli reduced miR-181b expression. Rescue of miR-181b levels by systemic administration of miR-181b "mimics" reduced downstream NF-κB signaling and leukocyte influx in the vascular endothelium and decreased lung injury and mortality in endotoxemic mice. In contrast, miR-181b inhibition exacerbated endotoxin-induced NF-κB activity, leukocyte influx, and lung injury. Finally, we observed that critically ill patients with sepsis had reduced levels of miR-181b compared with control intensive care unit (ICU) subjects. Collectively, these findings demonstrate that miR-181b regulates NF-κB-mediated EC activation and vascular inflammation in response to proinflammatory stimuli and that rescue of miR-181b expression could provide a new target for antiinflammatory therapy and critical illness.

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