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
{"title":"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。","authors":"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","doi":"10.1007/s12195-022-00723-1","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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 <i>in vitro</i> and in a nonhuman primate model of diet-induced atherosclerosis <i>in vivo</i>.</p><p><strong>Methods and results: </strong><i>In vitro</i>, 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 <i>in vivo</i>.</p><p><strong>Conclusion: </strong>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 <i>in vitro</i> and in atherosclerosis-prone carotid arteries <i>in vivo</i>. These findings suggest that TFKs may contribute to the pathogenesis of atherosclerosis and could represent a novel therapeutic target.</p>","PeriodicalId":9687,"journal":{"name":"Cellular and molecular bioengineering","volume":null,"pages":null},"PeriodicalIF":2.3000,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124262/pdf/12195_2022_Article_723.pdf","citationCount":"4","resultStr":"{\"title\":\"Ibrutinib Inhibits BMX-Dependent Endothelial VCAM-1 Expression <i>In Vitro</i> and Pro-Atherosclerotic Endothelial Activation and Platelet Adhesion <i>In Vivo</i>.\",\"authors\":\"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\",\"doi\":\"10.1007/s12195-022-00723-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>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 <i>in vitro</i> and in a nonhuman primate model of diet-induced atherosclerosis <i>in vivo</i>.</p><p><strong>Methods and results: </strong><i>In vitro</i>, 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 <i>in vivo</i>.</p><p><strong>Conclusion: </strong>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 <i>in vitro</i> and in atherosclerosis-prone carotid arteries <i>in vivo</i>. These findings suggest that TFKs may contribute to the pathogenesis of atherosclerosis and could represent a novel therapeutic target.</p>\",\"PeriodicalId\":9687,\"journal\":{\"name\":\"Cellular and molecular bioengineering\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2022-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124262/pdf/12195_2022_Article_723.pdf\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cellular and molecular bioengineering\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://doi.org/10.1007/s12195-022-00723-1\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOPHYSICS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular and molecular bioengineering","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1007/s12195-022-00723-1","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOPHYSICS","Score":null,"Total":0}
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.
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.