Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation

Antoine Abou Jaoude, Lise Badiqué, Mohamed Mlih, Sara Awan, Sunning Guo, Alexandre Lemle, Clauda Abboud, Sophie Foppolo, Lionel Host, Jérôme Terrand, Hélène Justiniano, Joachim Herz, Rachel L. Matz, Philippe Boucher

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4 Scopus citations

Abstract

ShcA is an adaptor protein that binds to the cytoplasmic tail of receptor tyrosine kinases and of the Low Density Lipoprotein-related receptor 1 (LRP1), a trans-membrane receptor that protects against atherosclerosis. Here, we examined the role of endothelial ShcA in atherosclerotic lesion formation. We found that atherosclerosis progression was markedly attenuated in mice deleted for ShcA in endothelial cells, that macrophage content was reduced at the sites of lesions, and that adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) were severely reduced. Our data indicate that transcriptional regulation of ShcA by the zinc-finger E-box-binding homeobox 1 (ZEB1) and the Hippo pathway effector YAP, promotes ICAM-1 expression independently of p-NF-κB, the primary driver of adhesion molecules expressions. In addition, ShcA suppresses endothelial Akt and nitric oxide synthase (eNOS) expressions. Thus, through down regulation of eNOS and ZEB1-mediated ICAM-1 up regulation, endothelial ShcA promotes monocyte-macrophage adhesion and atherosclerotic lesion formation. Reducing ShcA expression in endothelial cells may represent an obvious therapeutic approach to prevent atherosclerosis.

Original languageEnglish (US)
Article number4501
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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    Jaoude, A. A., Badiqué, L., Mlih, M., Awan, S., Guo, S., Lemle, A., Abboud, C., Foppolo, S., Host, L., Terrand, J., Justiniano, H., Herz, J., Matz, R. L., & Boucher, P. (2018). Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation. Scientific Reports, 8(1), [4501]. https://doi.org/10.1038/s41598-018-22819-3