Abstract Number: OC 58.4
Meeting: ISTH 2022 Congress
Background: Inflammatory activation of the vascular endothelium leads to the overexpression of adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1), contributing to the pro-thrombotic state underpinning atherogenesis. Although TEC family kinases (TFKs) mediate inflammatory cell and platelet activation, their contribution to vascular endothelial activation remain unclear.
Aims: Examine the role of TFK member, BMX, in endothelial cell (EC) activation in vitro and in atherosclerosis-prone carotid arteries of obese nonhuman primates (NHPs) in vivo.
Methods: Human aortic ECs (HAECs) were stimulated with vascular endothelial growth factors (VEGF)-A for 6 hours. BMX phosphorylation and VCAM-1 expression were measured by Western blot. To advance toward in vivo testing, two obese NHPs on a high-fat diet were administered the TFK inhibitor, ibrutinib orally daily for 7 days at 10 mg·kg−1·day−1 and studied at baseline, and days 1 and 7 after drug administration. We measured platelet activation and aggregation in primate samples in response to glycoprotein VI-agonist, cross-linked collagen-related peptide (CRP-XL). Contrast-enhanced ultrasound molecular imaging was used to measure platelet GPIbα and endothelial VCAM-1 expression at the carotid bifurcation in obese NHPs during treatment.
Results: VEGF-A increased VCAM-1 expression and induced phosphorylation of BMX in HAECs. Ibrutinib or BMX inhibitors eliminated the ability of VEGF-A to stimulate VCAM-1 expression in HAECs. In a NHP model of early atherosclerosis, platelet aggregation and activation in response to CRP-XL was abrogated following treatment with ibrutinib. Ibrutinib decreased the signal for both endothelial VCAM-1 and platelet GPIbα compare to baseline, in vivo.
Conclusion(s): Our studies demonstrate that VEGF-A signals through BMX to induce VCAM-1 expression and that VCAM-1 expression in HAECs is sensitive to ibrutinib. Treatment with ibrutinib decreased the markers of platelet deposition and endothelial cell activation in vivo. These findings suggest that TFKs may contribute to the pathogenesis of atherosclerosis and could represent a novel therapeutic target.
To cite this abstract in AMA style:Kohs T, Olson S, Jordan K, Zheng T, Xie A, Hodovan J, Muller M, McArthur C, Johnson J, Sousa B, Wallisch M, Kievit P, Aslan J, Seixas J, Bernardes G, Hinds M, Lindner J, McCarty O, Puy C, Shatzel J. Ibrutinib inhibits BMX-dependent endothelial VCAM-1 expression in vitro and pro-atherosclerotic endothelial activation and platelet adhesion in vivo [abstract]. https://abstracts.isth.org/abstract/ibrutinib-inhibits-bmx-dependent-endothelial-vcam-1-expression-in-vitro-and-pro-atherosclerotic-endothelial-activation-and-platelet-adhesion-in-vivo/. Accessed February 28, 2024.
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