Tanaka Jun, Qiang Li, Banks Alexander S, Welch Carrie L, Matsumoto Michihiro, Kitamura Tadahiro, Ido-Kitamura Yukari, DePinho Ronald A, Accili Domenico
Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Diabetes. 2009 Oct;58(10):2344-54. doi: 10.2337/db09-0167. Epub 2009 Jul 7.
Atherosclerotic cardiovascular disease is the leading cause of death among people with diabetes. Generation of oxidized LDLs and reduced nitric oxide (NO) availability because of endothelial NO synthase (eNOS) dysfunction are critical events in atherosclerotic plaque formation. Biochemical mechanism leading from hyperglycemia to oxLDL formation and eNOS dysfunction is unknown.
We show that glucose, acting through oxidative stress, activates the transcription factor Foxo1 in vascular endothelial cells.
Foxo1 promotes inducible NOS (iNOS)-dependent NO-peroxynitrite generation, which leads in turn to LDL oxidation and eNOS dysfunction. We demonstrate that Foxo1 gain-of-function mimics the effects of hyperglycemia on this process, whereas conditional Foxo1 knockout in vascular endothelial cells prevents it.
The findings reveal a hitherto unsuspected role of the endothelial iNOS-NO-peroxynitrite pathway in lipid peroxidation and eNOS dysfunction and suggest that Foxo1 activation in response to hyperglycemia brings about proatherogenic changes in vascular endothelial cell function.
动脉粥样硬化性心血管疾病是糖尿病患者的主要死因。氧化型低密度脂蛋白的生成以及由于内皮型一氧化氮合酶（eNOS）功能障碍导致的一氧化氮（NO）可用性降低是动脉粥样硬化斑块形成的关键事件。从高血糖到氧化型低密度脂蛋白形成和eNOS功能障碍的生化机制尚不清楚。
我们发现，葡萄糖通过氧化应激作用，激活血管内皮细胞中的转录因子Foxo1。
Foxo1促进诱导型一氧化氮合酶（iNOS）依赖性的NO-过氧亚硝酸盐生成，进而导致低密度脂蛋白氧化和eNOS功能障碍。我们证明，Foxo1功能获得模拟了高血糖对这一过程的影响，而血管内皮细胞中条件性Foxo1基因敲除可防止这种情况发生。
这些发现揭示了内皮iNOS-NO-过氧亚硝酸盐途径在脂质过氧化和eNOS功能障碍中迄今未被怀疑的作用，并表明高血糖反应中Foxo1激活导致血管内皮细胞功能发生促动脉粥样硬化改变。
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