FoxOs Integrate Pleiotropic Actions of Insulin in Vascular Endothelium to Protect Mice from Atherosclerosis

• Published in: Cell metabolism 2012-03, Vol.15 (3), p.372-381
• Main Authors: Tsuchiya, Kyoichiro, Tanaka, Jun, Shuiqing, Yu, Welch, Carrie L., DePinho, Ronald A., Tabas, Ira, Tall, Alan R., Goldberg, Ira J., Accili, Domenico
• Format: Article
• Language: English
• Subjects: Animals; Atherosclerosis - genetics; Atherosclerosis - prevention & control; Cells, Cultured; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Forkhead Box Protein O1; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Insulin - pharmacology; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Mice; Mice, Knockout; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2012.01.018

Atherosclerotic cardiovascular disease is the leading cause of death in insulin-resistant (type 2) diabetes. Vascular endothelial dysfunction paves the way for atherosclerosis through impaired nitric oxide availability, inflammation, and generation of superoxide. Surprisingly, we show that ablation of the three genes encoding isoforms of transcription factor FoxO in endothelial cells prevents atherosclerosis in low-density lipoprotein receptor knockout mice by reversing these subphenotypes. Paradoxically, the atheroprotective effect of FoxO deletion is associated with a marked decrease of insulin-dependent Akt phosphorylation in endothelial cells, owing to reduced FoxO-dependent expression of the insulin receptor adaptor proteins Irs1 and Irs2. These findings support a model in which FoxO is the shared effector of multiple atherogenic pathways in endothelial cells. FoxO ablation lowers the threshold of Akt activity required for protection from atherosclerosis. The data demonstrate that FoxO inhibition in endothelial cells has the potential to mediate wide-ranging therapeutic benefits for diabetes-associated cardiovascular disease. ► Knockout of the three Foxo genes prevents atherosclerosis in mice ► FoxO inactivation increases NO production, reduces inflammation and oxidative stress ► Akt activation by insulin is impaired in FoxO-deficient endothelial cells ► FoxOs control Irs1 and Irs2 expression in endothelial cells