1. Ibrutinib inhibits BMX-dependent endothelial VCAM-1 expression in vitro and pro-atherosclerotic endothelial activation and platelet adhesion in vivo
- Author
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Kohs, Tia C. L., Olson, Sven R., Pang, Jiaqing, Jordan, Kelley R., Zheng, Tony J., Xie, Aris, Hodovan, James, Muller, Matthew, McArthur, Carrie, Johnson, Jennifer, Sousa, Bárbara B., Wallisch, Michael, Kievit, Paul, Aslan, Joseph E., Seixas, João D., Bernardes, Gonçalo J. L., Hinds, Monica T., Lindner, Jonathan R., McCarty, Owen J. T., Puy, Cristina, Shatzel, Joseph J., Repositório da Universidade de Lisboa, Kohs, Tia CL [0000-0002-7900-0016], and Apollo - University of Cambridge Repository
- Subjects
BMX ,Endothelial cell ,BTK ,Modeling and Simulation ,Ibrutinib ,Platelet ,cardiovascular system ,Atherosclerosis ,TEC ,Tyrosine kinase ,General Biochemistry, Genetics and Molecular Biology - Abstract
© 2022 The Author(s) under exclusive licence to Biomedical Engineering Society., Introduction: 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., This work has been supported by grants from the National Institute of Health (R01HL101972, R01HL078610, R01HL130046, R01HL151367, P51OD011092). The Endocrine Technologies Core and Clinical Pathology Laboratory is supported (in part) by a National Institute of Health grant (P51OD011092) for operation of the ONPRC.
- Published
- 2022