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Atorvastatin prevents endothelial dysfunction in high glucose condition through Skp2-mediated degradation of FOXO1 and ICAM-1.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2018 Jan 08; Vol. 495 (2), pp. 2050-2057. Date of Electronic Publication: 2017 Aug 10. - Publication Year :
- 2018
-
Abstract
- Objective: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin has been reported to exert vasculo-protective action in diabetes. We investigated the vasculo-protective mechanism of atorvastatin by evaluating its effect on two major pathogenic molecules, FOXO1 and ICAM1, mediated by S-phase kinase-associated protein 2 (Skp2) in diabetic endothelial dysfunction. APPROACH AND RESULTS: [1] FOXO1: Hyperglycemic condition increased FOXO1 protein level in endothelial cells, which was reversed by atorvastatin. This atorvastatin effect was obliterated by treatment of protease inhibitor, suggesting that atorvastatin induces degradation of FOXO1. Immunoprecipitation showed that atorvastatin facilitated the binding of Skp2 to FOXO1, leading to ubiquitination and degradation of FOXO1. [2] ICAM-1: Increased ICAM1 in high glucose condition was reduced by atorvastatin. But this effect of atorvastatin was obliterated when Skp2 was inhibited, suggesting that atorvastatin enhances binding of Skp2 to ICAM1 leading to degradation. Actually, ubiquitination and degradation of ICAM-1 were reduced when Skp2 was inhibited. In vitro monocyte adhesion assay revealed that atorvastatin reduced monocyte adhesion on endothelial cells in high glucose condition, which was reversed by Skp2 knock-down.<br />Conclusion: Atorvastatin strengthens Skp2 binding to FOXO1 or ICAM1, leading to ubiquitination and degradation. Skp2-dependent ubiquitination of major pathogenic molecules is the key mechanism for statin's protective effect on endothelial function in diabetes.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Anticholesteremic Agents administration & dosage
Cells, Cultured
Dose-Response Relationship, Drug
Endothelial Cells pathology
Humans
Metabolic Networks and Pathways drug effects
Treatment Outcome
Atorvastatin administration & dosage
Endothelial Cells drug effects
Endothelial Cells immunology
Forkhead Box Protein O1 immunology
Glucose immunology
Intercellular Adhesion Molecule-1 immunology
S-Phase Kinase-Associated Proteins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 495
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 28802579
- Full Text :
- https://doi.org/10.1016/j.bbrc.2017.08.023