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

Autor:	Abou-Jaoude A; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Badiqué L; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Mlih M; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Awan S; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Guo S; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Lemle A; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Abboud C; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Foppolo S; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Host L; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Terrand J; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Justiniano H; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France., Herz J; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Matz RL; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France. rachel.matz-westphal@unistra.fr., Boucher P; CNRS, UMR 7213, University of Strasbourg, 67401, Illkirch, France. philippe.boucher@unistra.fr.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2018 Mar 14; Vol. 8 (1), pp. 4501. Date of Electronic Publication: 2018 Mar 14.
DOI:	10.1038/s41598-018-22819-3
Abstrakt:	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.
Databáze:	MEDLINE
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