Atorvastatin prevents endothelial dysfunction in high glucose condition through Skp2-mediated degradation of FOXO1 and ICAM-1

Abstract Objective The 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitor atorvastatinhas been reported to exert vasculo-protective action in diabetes. We investigated the vasculo-protective mechanism of atorvastatinby evaluating its effect on two major pathogenic molecules, FOXO1and ICAM1, mediated by S-phase kinase-associated protein 2 ( Skp2) in diabetic endothelial dysfunction. Approach and results [1] FOXO1: Hyperglycemic condition increased FOXO1protein level in endothelial cells, which was reversed by atorvastatin. This atorvastatineffect was obliterated by treatment of protease inhibitor, suggesting that atorvastatininduces degradation of FOXO1. Immunoprecipitation showed that atorvastatinfacilitated the binding of Skp2to FOXO1, leading to ubiquitinationand degradation of FOXO1. [2] ICAM-1: Increased ICAM1 in high glucose condition was reduced by atorvastatin. But this effect of atorvastatinwas obliterated when Skp2was inhibited, suggesting that atorvastatinenhances binding of Skp2to ICAM1 leading to degradation. Actually, ubiquitinationand degradation of ICAM-1were reduced when Skp2was inhibited. In vitro monocyte adhesion assay revealed that atorvastatinreduced monocyte adhesion on endothelial cells in high glucose condition, which was reversed by Skp2knock-down. Conclusion Atorvastatinstrengthens Skp2binding to FOXO1or ICAM1, leading to ubiquitinationand degradation. Skp2-dependent ubiquitinationof major pathogenic molecules is the key mechanism for statin's protective effect on endothelial function in diabetes.