Expression profile of apoptotic and proliferative proteins in hypoxic HUVEC treated with statins.
Expression profile of apoptotic and proliferative proteins in hypoxic HUVEC treated with statins.
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DOI：
10.3892/ijo.2014.2780
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发表时间：
2015-02
影响因子：
5.2
通讯作者：
Xiaochen Li;Xiansheng Liu;Yong-jian Xu;Yuanzhou He;Jin Liu;M. Xie
中科院分区：
文献类型：
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作者：
Xiaochen Li;Xiansheng Liu;Yong-jian Xu;Yuanzhou He;Jin Liu;M. Xie
血管内皮细胞过度增殖参与了肿瘤血管生成的病理生理过程，是肿瘤在缺氧适应中生长和扩散所必需的。越来越多的证据表明他汀类药物具有潜在的抗血管生成益处。然而，他汀类药物在血管内皮细胞中作用的细胞内信号传导机制尚不明确。本研究旨在探讨氟伐他汀对常氧和缺氧的人脐静脉内皮细胞（HUVEC）增殖和凋亡的影响。流式细胞仪分析显示，他汀类药物逆转缺氧诱导的细胞增殖，减缓G1到S转换和诱导细胞凋亡。为了进一步了解他汀类药物的下游效应，我们使用人凋亡抗体阵列测量了缺氧HUVEC中各种凋亡相关蛋白的表达。结果表明，在细胞凋亡过程中，caspase-3、p27、IGFBP-6表达上调，bcl-2、survivin表达下降。随后的研究证实了阵列的结果，并表明氟伐他汀通过增加bax/bcl-2的比例，释放细胞色素c，进而激活caspase-9和caspase-3，最终裂解PARP，从而激活线粒体凋亡。进一步的实验表明，氟伐他汀抑制细胞增殖与IGFBP-6、p27、p53水平升高和Survivin、cyclin B1、cyclin D1和VEGF表达降低有关。总之，氟伐他汀通过多种信号通路抑制缺氧条件下HUVEC的增殖并诱导其凋亡，为他汀类药物治疗肿瘤提供了理论依据。
Vascular endothelial hyperproliferation is involved in the pathophysiological process of angiogenesis, which is indispensable for tumor growth and spread in hypoxic adaptation. There is increasing evidence indicating that statins have potential anti-angiogenesis benefits. However, the intracellular signaling mechanism underlying the effect of statins in vascular endothelial cells is undefined. The present study was conducted to investigate the effect of fluvastatin on cell proliferation and apoptosis in normoxic and hypoxic human umbilical vein endothelial cells (HUVEC). Flow cytometric analyses revealed that statins reversed hypoxia-induced cell proliferation by slowing down G1 to S transition and inducing cell apoptosis. To get further insights into the downstream effects of statins, we measured the expression of various apoptosis-associated proteins in hypoxic HUVEC using human apoptosis antibody array. The results suggested that cell apoptosis was accompanied by upregulation of caspase-3, p27, IGFBP-6 and a decrease of bcl-2, survivin levels. Subsequent studies confirmed the results of array and demonstrated that fluvastatin activated mitochondrial apoptosis through enhancing bax/bcl-2 ratio, releasing cytochrome c, in turn activating caspase-9 and caspase-3, and eventually cleaving PARP. Further experiments showed that inhibition of cell proliferation by fluvastatin was associated with elevated IGFBP-6, p27, p53 levels and reduced survivin, cyclin B1, cyclin D1 and VEGF expression. Taken together, fluvastatin suppressed cell proliferation and induced apoptosis of HUVEC in hypoxia via multiple signaling pathways, providing a theoretical basis for statins in the therapy of cancer.