Diabetic LDL inhibits cell-cycle progression via STAT5B and p21waf
Diabetic LDL inhibits cell-cycle progression via STAT5B and p21waf
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DOI：
10.1172/jci200213617
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发表时间：
2002-01-01
影响因子：
15.9
通讯作者：
Pegoraro, L
中科院分区：
文献类型：
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作者：
Brizzi, MF;Dentelli, P;Pegoraro, L
修饰的低密度脂蛋白是糖尿病患者血管内皮损伤的主要原因。在本研究中，我们分析了从2型糖尿病患者(dm-LDL)或从非糖尿病受试者(n-LDL)中回收的低密度脂蛋白对血管内皮细胞的影响。用dm-低密度脂蛋白处理人脐静脉内皮细胞，而不用n-低密度脂蛋白处理人脐静脉内皮细胞，会导致细胞在G1期聚集。为了分析这种作用的分子机制，我们分析了细胞周期调节因子p21(WAF)的表达和功能，它是信号转导和转录激活因子(STAT)的靶标。DM-LDL导致瞬时STAT5磷酸化，形成含有STAT5的复合体，并在转录水平激活p21(WAF)的表达。显性-阴性形式的STAT5B的表达，而不是STAT5A的表达，显著降低了p21(WAF)的表达和G1期细胞的比例。最后，免疫荧光分析表明，激活的STAT5在新形成的斑块内血管和斑块管腔一侧的内皮细胞中表达。同样，p21(WAF)免疫反应在新生内膜血管中也被发现。我们的结果表明，STAT5B在糖尿病相关血管疾病中作为基因表达的调节因子发挥作用。
Modified LDL is a major cause of injury to the endothelium in diabetes. In the present study, we analyzed the effects on endothelial cells of LDL recovered from type 2 diabetic patients (dm-LDL) or from nondiabetic subjects (n-LDL). Treatment of human umbilical vein endothelial cells with dm-LDL, but not n-LDL, led to the accumulation of cells in G1. To dissect the molecular mechanisms of this effect, we analyzed the expression and function of the cyclin-dependent kinase inhibitor p21(waf), a cell cycle regulator known to be a target of the signal transducers and activators of transcription (STATs). dm-LDL led to transient STAT5 phosphorylation and the formation of a STAT5-containing complex and activated p21(waf) expression at the transcriptional level. Expression of the dominant-negative form of STAT5B, but not of STAT5A, significantly decreased both p21(waf) expression and the fraction of cells in G1. Finally, immunofluorescence analysis demonstrated that activated STAT5 is expressed in newly formed intraplaque vessels and in endothelial cells lining the luminal side of the plaque. Similarly, p21(waf) immunoreactivity was found in the neointimal vasculature. Our results suggest a role of STAT5B as a regulator of gene expression in diabetes-associated vascular disease.