Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Cell Metab. 2012 Mar 7;15(3):372-81. 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.
动脉粥样硬化性心血管疾病是胰岛素抵抗（2 型）糖尿病患者死亡的主要原因。血管内皮功能障碍通过减少一氧化氮的产生、炎症和超氧化物的生成，为动脉粥样硬化铺平了道路。令人惊讶的是，我们发现通过逆转这些亚表型，内皮细胞中编码转录因子 FoxO 同工型的三个基因的缺失可预防低密度脂蛋白受体敲除小鼠的动脉粥样硬化。矛盾的是，FoxO 缺失的抗动脉粥样硬化作用与内皮细胞中胰岛素依赖性 Akt 磷酸化的显著减少有关，这归因于 FoxO 依赖性胰岛素受体衔接蛋白 Irs1 和 Irs2 的表达减少。这些发现支持了一个模型，即 FoxO 是内皮细胞中多种动脉粥样硬化途径的共同效应因子。FoxO 的缺失降低了 Akt 活性预防动脉粥样硬化所需的阈值。这些数据表明，内皮细胞中 FoxO 的抑制有可能为与糖尿病相关的心血管疾病带来广泛的治疗益处。
