FOXO1 Mediates the Autocrine Effect of Endothelin-1 on Endothelial Cell Survival
FOXO1 Mediates the Autocrine Effect of Endothelin-1 on Endothelial Cell Survival
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DOI：
10.1210/me.2011-1276
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发表时间：
2012-07-01
影响因子：
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通讯作者：
Dong, H. Henry
中科院分区：
文献类型：
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作者：
Cifarelli, Vincenza;Lee, Sojin;Dong, H. Henry
慢性高血糖症对内皮产生有害影响，导致糖尿病控制不佳的内皮功能障碍和微血管并发症。为了了解潜在的机制，我们研究了内皮素-1（ET-1）对内皮细胞产生叉头框O 1（FOXO 1）的影响，FOXO 1是一种叉头转录因子，在细胞存活中起着重要作用。ET-1是主要由内皮分泌的21个氨基酸的肽。利用腺病毒介导的基因转移方法，我们将FOXO 1 cDNA导入培养的人主动脉内皮细胞。FOXO 1显示刺激B细胞白血病/淋巴瘤2相关死亡启动子（BAD）产生并促进细胞凋亡。这种作用被ET-1所抵消。在ET-1的作用下，FOXO 1被磷酸化并从细胞核转移到细胞质，从而抑制BAD的产生并减轻FOXO 1介导的细胞凋亡。高血压刺激FOXO 1的O-糖基化，并促进其在人主动脉内皮细胞的核定位。这种效应解释了细胞核中不受约束的FOXO 1活性，有助于在高血糖条件下增加BAD产生和内皮细胞凋亡。FOXO 1表达在链脲佐菌素诱导的糖尿病小鼠和糖尿病db/db小鼠的主动脉中变得失调。这种高血糖引起FOXO 1失调，其随后对内皮细胞存活的影响被ET-1纠正。同样，在胰岛素治疗降低高血糖后，糖尿病小鼠主动脉中FoxO 1的失调是可逆的。这些数据揭示了FOXO 1介导ET-1对内皮细胞存活的自分泌作用的机制。ET-1对内皮细胞FOXO 1活性的调控能力减弱，导致FOXO 1失调，可能是糖尿病高血糖诱导内皮细胞损伤的原因之一。（分子内分泌学26：1213-1224，2012）
Chronic hyperglycemia exerts a deleterious effect on endothelium, contributing to endothelial dysfunction and microvascular complications in poorly controlled diabetes. To understand the underlying mechanism, we studied the effect of endothelin-1 (ET-1) on endothelial production of Forkhead box O1 (FOXO1), a forkhead transcription factor that plays an important role in cell survival. ET-1 is a 21-amino acid peptide that is secreted primarily from endothelium. Using adenovirus-mediated gene transfer approach, we delivered FOXO1 cDNA into cultured human aorta endothelial cells. FOXO1 was shown to stimulate B cell leukemia/lymphoma 2-associated death promoter (BAD) production and promote cellular apoptosis. This effect was counteracted by ET-1. In response to ET-1, FOXO1 was phosphorylated and translocated from the nucleus to cytoplasm, resulting in inhibition of BAD production and mitigation of FOXO1-mediated apoptosis. Hyperglycemia stimulated FOXO1 O-glycosylation and promoted its nuclear localization in human aorta endothelial cells. This effect accounted for unbridled FOXO1 activity in the nucleus, contributing to augmented BAD production and endothelial apoptosis under hyperglycemic conditions. FOXO1 expression became deregulated in the aorta of both streptozotocin-induced diabetic mice and diabetic db/db mice. This hyperglycemia-elicited FOXO1 deregulation and its ensuing effect on endothelial cell survival was corrected by ET-1. Likewise, FoxO1 deregulation in the aorta of diabetic mice was reversible after the reduction of hyperglycemia by insulin therapy. These data reveal a mechanism by which FOXO1 mediated the autocrine effect of ET-1 on endothelial cell survival. FOXO1 deregulation, resulting from an impaired ability of ET-1 to control FOXO1 activity in endothelium, may contribute to hyperglycemia-induced endothelial lesion in diabetes. (Molecular Endocrinology 26: 1213-1224, 2012)