High glucose concentrations alter hypoxia-induced control of vascular smooth muscle cell growth via a HIF-1α-dependent pathway
High glucose concentrations alter hypoxia-induced control of vascular smooth muscle cell growth via a HIF-1α-dependent pathway
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DOI：
10.1016/j.yjmcc.2006.12.006
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发表时间：
2007-03-01
影响因子：
5
通讯作者：
Cahill, Paul A.
中科院分区：
文献类型：
--
作者：
Gao, Wei;Ferguson, Gail;Cahill, Paul A.
糖尿病的诱导可在血管病变形成前引起动脉壁缺氧。因此，我们确定了高血糖与缺氧的主要调节因子-缺氧诱导因子1- α (HIF-1 α)在体外控制缺氧诱导的血管平滑肌细胞生长中是否存在动态相互作用。将牛主动脉平滑肌细胞（BASMC）暴露于正常葡萄糖（5.5 mM）和高血糖（25 mM葡萄糖）条件下，在常氧（5% CO2, 95%空气）和低氧（2% O-2, 5% CO2, 93% N-2）条件下5天，然后使用FACS分析，免疫印迹QRT-PCR和caspase-3酶活性检测细胞增殖和凋亡。在正常葡萄糖存在的情况下，慢性缺氧刺激细胞凋亡，抑制细胞增殖，而高血糖显著减弱缺氧诱导的生长反应。HIF-1 α的表达也受到高血糖的抑制，同时缺氧反应元件（HRE）启动子的激活降低。在正常葡萄糖存在的情况下，HIF-1 α的siRNA敲低抑制了缺氧诱导的生长变化，同时减弱了高血糖对缺氧诱导反应的影响。这些结果表明，高血糖通过抑制HIF-1 α的表达和活性改变了缺氧诱导的血管细胞生长的变化。(c) 2007爱思唯尔公司版权所有。
Induction of diabetes can produce arterial wall hypoxia preceding the formation of vascular lesions. We therefore determined whether a dynamic interplay exists between hyperglycemia and the major regulator of hypoxia, hypoxia-inducible factor 1-alpha (HIF-1 alpha) in controlling hypoxia-induced vascular smooth muscle cell growth in vitro. Bovine aortic smooth muscle cells (BASMC) were exposed to conditions of normal glucose (5.5 mM) and hyperglycemia (25 mm glucose) under normoxic (5% CO2, 95% air) and hypoxic (2% O-2, 5% CO2, 93% N-2) conditions for 5 days prior to determining cell proliferation and apoptosis using FACS analysis, immunoblot QRT-PCR and caspase-3 enzymatic activity. Chronic hypoxia stimulated apoptosis and inhibited proliferation in the presence of normal glucose while hyperglycemia significantly attenuated the hypoxic-induced growth response. HIF-1 alpha expression was also inhibited by hyperglycemia with a concomitant decrease in hypoxia response element (HRE) promoter transactivation. Subsequent siRNA knockdown of HIF-1 alpha inhibited the hypoxia-induced changes in growth in the presence of normal glucose while concomitantly attenuating the effects of hyperglycemia on the hypoxic-induced response. These results suggest that hypoxia-induced changes in vascular cell growth are altered by hyperglycemia via inhibition of HIF-1 alpha expression and activity. (c) 2007 Elsevier Inc. All rights reserved.