Show simple item record

dc.contributor.authorKohs, Tia CL
dc.contributor.authorOlson, Sven R
dc.contributor.authorPang, Jiaqing
dc.contributor.authorJordan, Kelley R
dc.contributor.authorZheng, Tony J
dc.contributor.authorXie, Aris
dc.contributor.authorHodovan, James
dc.contributor.authorMuller, Matthew
dc.contributor.authorMcArthur, Carrie
dc.contributor.authorJohnson, Jennifer
dc.contributor.authorSousa, Bárbara B
dc.contributor.authorWallisch, Michael
dc.contributor.authorKievit, Paul
dc.contributor.authorAslan, Joseph E
dc.contributor.authorSeixas, João D
dc.contributor.authorLopes Bernardes, Goncalo
dc.contributor.authorHinds, Monica T
dc.contributor.authorLindner, Jonathan R
dc.contributor.authorMcCarty, Owen JT
dc.contributor.authorPuy, Cristina
dc.contributor.authorShatzel, Joseph J
dc.date.accessioned2022-03-28T23:30:17Z
dc.date.available2022-03-28T23:30:17Z
dc.date.issued2022-06
dc.identifier.issn1865-5025
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335446
dc.description.abstractIntroduction: Inflammatory activation of the vascular endothelium leads to overexpression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), contributing to the pro-thrombotic state underpinning atherogenesis. While the role of TEC family kinases (TFKs) in mediating inflammatory cell and platelet activation is well defined, the role of TFKs in vascular endothelial activation remains unclear. We investigated the role of TFKs in endothelial cell activation in vitro and in a nonhuman primate model of diet-induced atherosclerosis in vivo. Methods and Results: In vitro, we found that ibrutinib blocked activation of the TFK member, BMX, by vascular endothelial growth factors (VEGF)-A in human aortic endothelial cells (HAECs). Blockade of BMX activation with ibrutinib or pharmacologically distinct BMX inhibitors eliminated the ability of VEGF-A to stimulate VCAM-1 expression in HAECs. We validated that treatment with ibrutinib inhibited TFK-mediated platelet activation and aggregation in both human and primate samples as measured using flow cytometry and light transmission aggregometry. We utilized contrast-enhanced ultrasound molecular imaging to measure platelet GPIbα and endothelial VCAM-1 expression in atherosclerosis-prone carotid arteries of obese nonhuman primates. We observed that the TFK inhibitor, ibrutinib, inhibited platelet deposition and endothelial cell activation in vivo. Conclusion: Herein we found that VEGF-A signals through BMX to induce VCAM-1 expression in endothelial cells, and that VCAM-1 expression is sensitive to ibrutinib in vitro and in atherosclerosis-prone carotid arteries in vivo. These findings suggest that TFKs may contribute to the pathogenesis of atherosclerosis and could represent a novel therapeutic target.
dc.description.sponsorshipNational Institute of Health (R01HL101972, R01HL078610, R01HL130046, R01HL151367, P51OD011092). National Institute of Health grant (P51OD011092).
dc.publisherSpringer Science and Business Media LLC
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.titleIbrutinib Inhibits BMX-Dependent Endothelial VCAM-1 Expression In Vitro and Pro-Atherosclerotic Endothelial Activation and Platelet Adhesion In Vivo.
dc.typeArticle
dc.publisher.departmentDepartment of Chemistry
dc.date.updated2022-03-25T14:50:42Z
prism.publicationNameCell Mol Bioeng
dc.identifier.doi10.17863/CAM.82875
dcterms.dateAccepted2022-03-24
rioxxterms.versionofrecord10.1007/s12195-022-00723-1
rioxxterms.versionAM
dc.contributor.orcidKohs, Tia CL [0000-0002-7900-0016]
dc.contributor.orcidLopes Bernardes, Goncalo [0000-0001-6594-8917]
dc.identifier.eissn1865-5033
rioxxterms.typeJournal Article/Review
cam.issuedOnline2022-04-18
cam.orpheus.successWed May 25 11:13:27 BST 2022 - Embargo updated
cam.orpheus.counter2
cam.depositDate2022-03-25
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2023-04-18


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record