Disparate effects of simvastatin on angiogenesis during hypoxia and inflammation.
OBJECTIVE
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.


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 micromol/L) and mevalonate. HUVEC angiogenesis was evaluated by tube formation, migration, and proliferation assays. Hypoxia inducible factor (HIF)-1alpha, vascular endothelial growth factor (VEGF), Akt, endothelium nitric oxide synthase (e-NOS), and oxidative stress were evaluated.


RESULTS
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-1alpha, 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.


CONCLUSIONS
We conclude that at the same dosage, simvastatin can either promote or inhibit angiogenesis, possibly by activating upstream regulators of HIF-1alpha in hypoxia, but conversely interfering with angiogenic signaling downstream to inflammation. These opposing angiogenic effects should be considered in the therapeutic strategies with statins.
Zhu
Xiang-Yang
XY
Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, United States.
Daghini
Elena
E
Chade
Alejandro R
AR
Lavi
Ronit
R
Napoli
Claudio
C
Lerman
Amir
A
Lerman
Lilach O
LO
D015687:Cell Hypoxia; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019821:Simvastatin / Q000009:adverse effects / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000960:Hypolipidemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin