Expression profile of apoptotic and proliferative proteins in hypoxic HUVEC treated with statins

Li,Xiaochen; Liu,Xiansheng; Xu,Yongjian; He,Yuanzhou; Liu,Jin; Xie,Min

doi:10.3892/ijo.2014.2780

Expression profile of apoptotic and proliferative proteins in hypoxic HUVEC treated with statins

Authors:
- Xiaochen Li
- Xiansheng Liu
- Yongjian Xu
- Yuanzhou He
- Jin Liu
- Min Xie
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Affiliations: Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
Published online on: November 26, 2014 https://doi.org/10.3892/ijo.2014.2780
Pages: 677-684

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Abstract

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.

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