伊鲁替尼体外抑制bmx依赖性内皮细胞VCAM-1表达和体内促动脉粥样硬化内皮细胞活化和血小板粘附。

IF 2.3 4区 医学 Q3 BIOPHYSICS
Tia C L Kohs, Sven R Olson, Jiaqing Pang, Kelley R Jordan, Tony J Zheng, Aris Xie, James Hodovan, Matthew Muller, Carrie McArthur, Jennifer Johnson, Bárbara B Sousa, Michael Wallisch, Paul Kievit, Joseph E Aslan, João D Seixas, Gonçalo J L Bernardes, Monica T Hinds, Jonathan R Lindner, Owen J T McCarty, Cristina Puy, Joseph J Shatzel
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引用次数: 4

摘要

血管内皮的炎症激活导致粘附分子如血管细胞粘附分子-1 (VCAM-1)的过度表达,促进血栓形成状态,支持动脉粥样硬化的发生。虽然TEC家族激酶(TFKs)在介导炎症细胞和血小板活化中的作用已被明确,但TFKs在血管内皮活化中的作用仍不清楚。我们在体外研究了TFKs在内皮细胞激活中的作用,并在非人类灵长类动物饮食诱导的动脉粥样硬化模型中进行了研究。方法和结果:在体外,我们发现依鲁替尼阻断了人主动脉内皮细胞(HAECs)中血管内皮生长因子(VEGF)-A对TFK成员BMX的激活。用依鲁替尼或药理学上不同的BMX抑制剂阻断BMX激活,消除了VEGF-A刺激haec中VCAM-1表达的能力。我们通过流式细胞术和光透射聚集术验证了伊鲁替尼治疗可以抑制tfk介导的血小板活化和聚集。我们利用超声分子成像技术检测了肥胖非人灵长类动物颈动脉粥样硬化易发动脉中血小板GPIbα和内皮细胞VCAM-1的表达。我们观察到TFK抑制剂伊鲁替尼在体内抑制血小板沉积和内皮细胞活化。结论:本研究发现VEGF-A通过BMX信号诱导内皮细胞中VCAM-1的表达,体外和体内易发生动脉粥样硬化的颈动脉中VCAM-1的表达对依鲁替尼敏感。这些发现表明,TFKs可能参与动脉粥样硬化的发病机制,并可能代表一种新的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Ibrutinib Inhibits BMX-Dependent Endothelial VCAM-1 Expression <i>In Vitro</i> and Pro-Atherosclerotic Endothelial Activation and Platelet Adhesion <i>In Vivo</i>.

Ibrutinib Inhibits BMX-Dependent Endothelial VCAM-1 Expression In Vitro and Pro-Atherosclerotic Endothelial Activation and Platelet Adhesion In Vivo.

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.

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来源期刊
CiteScore
5.60
自引率
3.60%
发文量
30
审稿时长
>12 weeks
期刊介绍: The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.
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