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

Research output: Contribution to journalArticle

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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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Intercellular Adhesion Molecule-1
Monocytes
Atherosclerosis
Endothelial Cells
Nitric Oxide Synthase Type III
Macrophages
LDL Receptors
Cytoplasmic and Nuclear Receptors
Protein-Tyrosine Kinases
Tail
Up-Regulation
Down-Regulation
Membranes
oxidized low density lipoprotein
Src Homology 2 Domain-Containing, Transforming Protein 1
Proteins
Zinc Finger E-box-Binding Homeobox 1
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation. / Jaoude, Antoine Abou; Badiqué, Lise; Mlih, Mohamed; Awan, Sara; Guo, Sunning; Lemle, Alexandre; Abboud, Clauda; Foppolo, Sophie; Host, Lionel; Terrand, Jérôme; Justiniano, Hélène; Herz, Joachim; Matz, Rachel L.; Boucher, Philippe.

In: Scientific Reports, Vol. 8, No. 1, 4501, 01.12.2018.

Research output: Contribution to journalArticle

Jaoude, AA, Badiqué, L, Mlih, M, Awan, S, Guo, S, Lemle, A, Abboud, C, Foppolo, S, Host, L, Terrand, J, Justiniano, H, Herz, J, Matz, RL & 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, vol. 8, no. 1, 4501. https://doi.org/10.1038/s41598-018-22819-3
Jaoude, Antoine Abou ; Badiqué, Lise ; Mlih, Mohamed ; Awan, Sara ; Guo, Sunning ; Lemle, Alexandre ; Abboud, Clauda ; Foppolo, Sophie ; Host, Lionel ; Terrand, Jérôme ; Justiniano, Hélène ; Herz, Joachim ; Matz, Rachel L. ; Boucher, Philippe. / Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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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.",
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AU - Herz, Joachim

AU - Matz, Rachel L.

AU - Boucher, Philippe

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