Cholesterol binding to VCAM-1 promotes vascular inflammation.

Autor: Kennelly JP; Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA.; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.; These authors contributed equally., Xiao X; Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA.; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.; These authors contributed equally., Gao Y; Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA.; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA., Kim S; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea., Hong SG; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.; Department of Medicine, Division of Cardiology, UCLA, Los Angeles, CA, USA., Villanueva M; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA., Ferrari A; Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA.; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA., Vanharanta L; Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.; Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland., Nguyen A; Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA.; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.; Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA., Nagari RT; Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA.; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA., Burton NR; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.; Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States., Tol MJ; Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA.; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA., Becker AP; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA., Lee MJ; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea., Ikonen E; Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.; Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland., Backus KM; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.; Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States.; DOE Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095, United States.; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, United States.; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, California 90095, United States., Mack JJ; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.; Department of Medicine, Division of Cardiology, UCLA, Los Angeles, CA, USA., Tontonoz P; Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA.; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 18. Date of Electronic Publication: 2024 Sep 18.
DOI: 10.1101/2024.09.17.613543
Abstrakt: Hypercholesterolemia has long been implicated in endothelial cell (EC) dysfunction, but the mechanisms by which excess cholesterol causes vascular pathology are incompletely understood. Here we used a cholesterol-mimetic probe to map cholesterol-protein interactions in primary human ECs and discovered that cholesterol binds to and stabilizes the adhesion molecule VCAM-1. We show that accessible plasma membrane (PM) cholesterol in ECs is acutely responsive to inflammatory stimuli and that the nonvesicular cholesterol transporter Aster-A regulates VCAM-1 stability in activated ECs by controlling the size of this pool. Deletion of Aster-A in ECs increases VCAM-1 protein, promotes immune cell recruitment to vessels, and impairs pulmonary immune homeostasis. Conversely, depleting cholesterol from the endothelium in vivo dampens VCAM-1 induction in response to inflammatory stimuli. These findings identify cholesterol binding to VCAM-1 as a key step during EC activation and provide a biochemical explanation for the ability of excess membrane cholesterol to promote immune cell recruitment to the endothelium.
Databáze: MEDLINE