Disparate effects of simvastatin on angiogenesis during hypoxia and inflammation

LIFE SCIENCES

卷:83

Article

Zhu, Xiang-Yang¹  Daghini, Elena¹  Chade, Alejandro R.¹  Lavi, Ronit¹  Napoli, Claudio^3,4  Lerman, Amir²  Lerman, Lilach O.^1,2 

[1] Mayo Clin, Coll Med, Div Nephrol & Hypertens, Dept Internal Med, Rochester, MN 55905 USA

[2] Mayo Clin, Coll Med, Div Cardiovasc Dis, Dept Internal Med, Rochester, MN 55905 USA

[3] Univ Naples 2, Sch Med, Dept Gen Pathol, Naples, Italy

[4] Univ Naples 2, Sch Med, Excellence Res Ctr Cardiovasc Dis, Naples, Italy

关键词: Simvastatin;    Hypoxia;    Angiogenesis;    Inflammation;   

DOI  :  10.1016/j.lfs.2008.09.029

来源: Elsevier

【 摘 要 】

Aims: Studies have shown that some of statin's pleiotropic effects were achieved by either promotion or inhibition of angiogenesis, depending on the underlying disease. This study tested the hypothesis that the angiogenic potential of simvastatin is related to the microenvironmental conditions. Main methods: Human umbilical vein endothelial cells (HUVEC) were studied after exposure to hypoxia or the inflammatory factors tumor necrosis factor (TNF)-alpha, with or without co-incubation with simvastatin (1 mu mol/L) and mevalonate. HUVEC angiogenesis was evaluated by tube formation. migration. and proliferation assays. Hypoxia inducible factor (HIF)-1 alpha, vascular endothelial growth factor (VEGF), Akt, endothelium nitric oxide synthase (e-NOS), and oxidative stress were evaluated. Key findings: HUVEC angiogenesis increased during hypoxia (tube length 14.7 +/- 0.5 vs. 7.8 +/- 0.6 mm, p<0.05) and further enhanced by simmastatin (19.3 +/- 1.1 mm, p<0.05 vs. hypoxia alone), which downregulated the expression of the HIF-1 inhibitor PHD2 and upregulated HIF-1 alpha, VEGF, and Akt, without changing oxidative stress or eNOS. Incubation with TNF-alpha promoted HUVEC angiogenesis (7.4 +/- 0.2 vs. 6.5 +/- 0.2 mm, p<0.05) with increased oxidative stress. However, simvastatin inhibited this promotion (2.5 +/- 0.3 mm, p<0.001 vs. TNF-alpha alone) by decreasing oxidative stress, VEGF, Akt, and eNOS. Significance: We conclude that at the same dosage, simvastatin can either promote or inhibit angiogenesis, possibly by activating upstream regulators of HIF-1 alpha in hypoxia, but conversely interfering with angiogenic signaling downstream to inflammation. These opposing angiogenic effects should be considered in the therapeutic strategies with statins. (C) 2008 Elsevier Inc. All rights reserved.

【 授权许可】

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