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Selective role of Nck1 in atherogenic inflammation and plaque formation
Mabruka Alfaidi, … , James G. Traylor, A. Wayne Orr
Mabruka Alfaidi, … , James G. Traylor, A. Wayne Orr
Published May 19, 2020
Citation Information: J Clin Invest. 2020;130(8):4331-4347. https://doi.org/10.1172/JCI135552.
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Research Article Cell biology Vascular biology Article has an altmetric score of 9

Selective role of Nck1 in atherogenic inflammation and plaque formation

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Abstract

Although the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) established the role of treating inflammation in atherosclerosis, our understanding of endothelial activation at atherosclerosis-prone sites remains limited. Disturbed flow at atheroprone regions primes plaque inflammation by enhancing endothelial NF-κB signaling. Herein, we demonstrate a role for the Nck adaptor proteins in disturbed flow–induced endothelial activation. Although highly similar, only Nck1 deletion, but not Nck2 deletion, limited flow-induced NF-κB activation and proinflammatory gene expression. Nck1-knockout mice showed reduced endothelial activation and inflammation in both models, disturbed flow– and high fat diet–induced atherosclerosis, whereas Nck2 deletion did not. Bone marrow chimeras confirmed that vascular Nck1, but not hematopoietic Nck1, mediated this effect. Domain-swap experiments and point mutations identified the Nck1 SH2 domain and the first SH3 domain as critical for flow-induced endothelial activation. We further characterized Nck1’s proinflammatory role by identifying interleukin 1 type I receptor kinase-1 (IRAK-1) as a Nck1-selective binding partner, demonstrating that IRAK-1 activation by disturbed flow required Nck1 in vitro and in vivo, showing endothelial Nck1 and IRAK-1 staining in early human atherosclerosis, and demonstrating that disturbed flow–induced endothelial activation required IRAK-1. Taken together, our data reveal a hitherto unknown link between Nck1 and IRAK-1 in atherogenic inflammation.

Authors

Mabruka Alfaidi, Christina H. Acosta, Dongdong Wang, James G. Traylor, A. Wayne Orr

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Figure 3

Ablation of Nck1, but not Nck2, blunts partial carotid ligation–induced inflammation.

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Ablation of Nck1, but not Nck2, blunts partial carotid ligation–induced ...
(A) Schematic of the study in which 4 groups of mice were subjected to the ligation surgery at the indicated time. (B) Endothelial mRNA analysis from iEC-Control, Nck1-KO, iEC-Nck2-KO, and iEC-Nck1/2-DKO mice. mRNA from the ligated left carotid (LC) was normalized to the unligated right carotid (RC) and to the housekeeping gene β-microglobulin. **P < 0.01; ***P < 0.001 by 2-way ANOVA followed by Bonferroni’s post hoc test. (C–F) ICAM-1 (red) and VCAM-1 (white) in the ligated left carotid compared with the unligated right carotid arteries among experimental groups. Endothelial cells were stained for von Willebrand factor (vWF in the dashed boxes) and the nuclei counterstained with DAPI. Scale bars: 200 μm (left 2 columns in C and E) and 50 μm (right columns). Images analyzed using NIS Elements software, from n = 7–10 mice/group. Data are the mean ± SEM. **P < 0.01; ***P < 0.001; ****P < 0.0001 by 1-way ANOVA followed by Tukey’s post hoc test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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