The calcium channel blocker cilnidipine selectively suppresses hypoxia-inducible factor 1 activity in vascular cells
The calcium channel blocker cilnidipine selectively suppresses hypoxia-inducible factor 1 activity in vascular cells
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DOI：
10.1016/j.ejphar.2009.01.012
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发表时间：
2009-03-15
影响因子：
5
通讯作者：
Hirota, Kiichi
中科院分区：
文献类型：
--
作者：
Oda, Seiko;Oda, Tomoyuki;Hirota, Kiichi
钙离子是包括低氧信号在内的细胞信号转导中最重要的第二信使之一。在本研究中，我们研究了L类钙通道阻滞剂硝苯地平、伊福地平、西尼地平、地尔硫卓和维拉帕米对低氧诱导基因表达的关键转录因子--缺氧诱导因子-1活性的影响。使用肺癌细胞系A549细胞、人主动脉平滑肌细胞和人脐静脉内皮细胞，我们证明西尼地平以一种细胞类型特异性的方式特异性地抑制HIF-1的活性和下游基因的表达。我们还证明了西尼地平抑制HIF-1α蛋白的合成不是通过影响细胞内低氧敏感元件Pro羟基酶的活性，而是抑制Akt和氮激活的蛋白激酶的活性，并且这种抑制不依赖于钙稳态的影响。(C)2009爱思唯尔B.V.保留所有权利。
Calcium ion is one of the most important second messengers of cellular signal transduction including hypoxia-elicited signals. in this study, we investigated the effects of the L-type calcium channel blockers such as nifedipine, efonidipine cilnidipine, diltiazem, and verapamil, on the activity of hypoxia-inducible factor-1 (HIF-1), a key transcription factor in control of hypoxia-induced gene expression. Using the lung carcinoma cell line A549 cells, human aortic smooth muscle cells, and human umbilical vein endothelial cells, we demonstrated that cilnidipine exclusively suppressed HIF-1 activity and the expressions of downstream genes in a cell-type specific manner. We also demonstrated that cilnidipine blocked the synthesis of the HIF-1 alpha Protein not by affecting activity of the intracellular hypoxia-sensing element prolyl hydroxylases but inhibiting activity of Akt and nitrogen-activated protein kinase and that the inhibition is not dependent on the effect oil calcium homeostasis. (C) 2009 Elsevier B.V. All rights reserved.