Inhibition of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension

Hameed, Abdul; Arnold, Nadine; Chamberlain, Janet; Pickworth, Josephine; Paiva, Cláudia; Dawson, Sarah; Cross, Simon S.; Lü, Long; Zhao, Lan; Morrell, Nicholas W.; Crossman, David C.; Newman, Christopher M.; Kiely, David G.; Francis, Sheila E.; Lawrie, Allan

doi:10.1084/jem.20112716

Cited by 85 publications

(124 citation statements)

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“…29,30 Notably, the expression of TRAIL and its receptors are markedly enhanced in PASMCs from patients with PAH and animal models and facilitate disease progression. 31 These findings suggest that osteoprotegerin may interact with other novel signaling pathways to promote PASMC proliferation rather than solely function as a TRAIL decoy receptor. Many studies, including those of the pulmonary vasculature, indicate that α v β 3 integrin activation promotes SMC proliferation, migration, and survival.…”

Section: Discussionmentioning

confidence: 95%

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

Jia

Zhu

Liu

et al. 2017

Circ Cardiovasc Genet

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Background-Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity. Methods and Results-Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416-and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416-induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin α v β 3 to elicit downstream focal adhesion kinase and AKT pathway activation. Conclusions-Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease. Jia et al Osteoprotegerin in Pulmonary HypertensionIn addition, experimental results indicated that osteoprotegerin promotes the proliferation of various cancer cells and endothelial cells in a TRAIL-independent manner. 14,15 These data expand the functional significance of osteoprotegerin beyond its presumed role as a receptor activator of nuclear factor-κB ligand and TRAIL decoy receptor, and suggest that it may interact with integrins or fatty acid synthase. 8,14,15 This is greatly relevant because pulmonary arterial smooth muscle cells (PASMCs) express several integrin molecules that regulate pulmonary vascular remodeling and contribute to PAH progression. 16,17 Integrins are a large family of structurally related heterodimeric transmembrane receptors that regulate cell-cell and cell-matrix contacts. 18 Of the 18α and 8β subtypes identified, pulmonary vascular smooth muscles express α 1-5 , α 7 , α 8 , α v , β 1 , β 3 , and β 4 .17 On the basis of these observations, we hypothesize that osteoprotegerin may contribute to pulmonary vascular remodeling in an integrindependent manner.In this study, we demonstrated that osteoprotegerin expression was increased in both murine and human pulmonary arterial SMCs (mPASMCs and hPASMCs) in response to hypoxia and in the lung tissue and pulmonary arteries of hypoxia plus SU5416 (HySu)-induced PAH model mice. Moreover, integrin α 1 , α 8 , α v , and β 3 express...

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Section: Discussionmentioning

confidence: 95%

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

Jia

Zhu

Liu

et al. 2017

Circ Cardiovasc Genet

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“…Further investigation is required to clarify whether IL13Ra2 contributes to resistance to apoptosis and survival by sequestering FAM120A from the TRAIL complex in addition to the activation of PI3K. On the other hand, TRAIL signaling promotes a proinflammatory pathway (25) that can establish a relationship with a similar IL13 activity. Finally, FAM120A showed an association with GPR56, a G-protein-coupled receptor for type III collagen, which activates the RHOA pathway (26).…”

Section: Discussionmentioning

confidence: 99%

IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis

et al. 2015

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IL13 signaling through its receptor IL13Ra2 plays a critical role in colon cancer invasion and liver metastasis, but the mechanistic features of this process are obscure. In this study, we identified a scaffold protein, FAM120A (C9ORF10), as a signaling partner in this process. FAM120A was overexpressed in human colon cancer cell lines and 55% of human colon cancer specimens. IL13Ra2-FAM120A coimmunoprecipitation experiments revealed further signaling network associations that could regulate the activity of IL13Ra2, including FAK, SRC, PI3K, G-protein-coupled receptors, and TRAIL receptors. In addition, FAM120A associated with kinesins and motor proteins involved in cargo movement along microtubules. IL13Ra2-triggered activation of the FAK and PI3K/AKT/mTOR pathways was mediated by FAM120A, which also recruited PI3K and functioned as a scaffold protein to enable phosphorylation and activation of PI3K by Src family kinases. FAM120A silencing abolished IL13-induced cell migration, invasion, and survival. Finally, antibody blockade of IL13Ra2 or FAM120A silencing precluded liver colonization in nude mice or metastasis. In conclusion, we identified FAM120A in the IL13/IL13Ra2 signaling pathway as a key mediator of invasion and liver metastasis in colon cancer. Cancer Res; 75(12); 2434-44. Ó2015 AACR.

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“…Thus all images were acquired at the same time point of the cycle, the end of diastole, to avoid scanning during the dilation of the aorta during systole. Transthoracic echocardiography was carried out using a commercial system (Vevo 770® with a RMV707B scan head, Visual Sonics, Toronto, Canada) as described 25 . Briefly mice were anaesthetised with isoflurane via oxygen before being placed supine on a heated platform and covered to minimise heat loss.…”

Section: Vascular Geometry and Heart Rate Measurementsmentioning

confidence: 99%

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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Inhibition of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension

Abstract: Genetic deletion of TRAIL or antibody blockade prevents the development of pulmonary arterial hypertension and can reverse vascular remodeling in established disease.

Cited by 85 publications

References 88 publications

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis

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

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Inhibition of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension

Abstract: Genetic deletion of TRAIL or antibody blockade prevents the development of pulmonary arterial hypertension and can reverse vascular remodeling in established disease.

Cited by 85 publications

References 88 publications

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α v β 3 /FAK/AKT Pathway Suppression

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α v β 3 /FAK/AKT Pathway Suppression

IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis

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

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Product

Resources

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Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression