TY - JOUR
T1 - Disparate effects of simvastatin on angiogenesis during hypoxia and inflammation
AU - Zhu, Xiang Yang
AU - Daghini, Elena
AU - Chade, Alejandro R.
AU - Lavi, Ronit
AU - Napoli, Claudio
AU - Lerman, Amir
AU - Lerman, Lilach O.
N1 - Funding Information:
This study was partly supported by NIH grant numbers DK-73608, HL77131, and DK77013, PO1HL085307, and an unrestricted medical school grant from Merck Pharmaceuticals.
PY - 2008/12/5
Y1 - 2008/12/5
N2 - 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)-α, with or without co-incubation with simvastatin (1 μmol/L) and mevalonate. HUVEC angiogenesis was evaluated by tube formation, migration, and proliferation assays. Hypoxia inducible factor (HIF)-1α, 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 simvastatin (19.3 ± 1.1 mm, p < 0.05 vs. hypoxia alone), which downregulated the expression of the HIF-1 inhibitor PHD2 and upregulated HIF-1α, VEGF, and Akt, without changing oxidative stress or eNOS. Incubation with TNF-α 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-α 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-1α in hypoxia, but conversely interfering with angiogenic signaling downstream to inflammation. These opposing angiogenic effects should be considered in the therapeutic strategies with statins.
AB - 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)-α, with or without co-incubation with simvastatin (1 μmol/L) and mevalonate. HUVEC angiogenesis was evaluated by tube formation, migration, and proliferation assays. Hypoxia inducible factor (HIF)-1α, 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 simvastatin (19.3 ± 1.1 mm, p < 0.05 vs. hypoxia alone), which downregulated the expression of the HIF-1 inhibitor PHD2 and upregulated HIF-1α, VEGF, and Akt, without changing oxidative stress or eNOS. Incubation with TNF-α 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-α 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-1α in hypoxia, but conversely interfering with angiogenic signaling downstream to inflammation. These opposing angiogenic effects should be considered in the therapeutic strategies with statins.
KW - Angiogenesis
KW - Hypoxia
KW - Inflammation
KW - Simvastatin
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U2 - 10.1016/j.lfs.2008.09.029
DO - 10.1016/j.lfs.2008.09.029
M3 - Article
C2 - 18976673
AN - SCOPUS:55749092758
SN - 0024-3205
VL - 83
SP - 801
EP - 809
JO - Life Sciences
JF - Life Sciences
IS - 23-24
ER -