Stimulatory effects of low-dose 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor fluvatatin on hepatocyte growth factor-induced angiogenesis: Involvement of p38 mitogen-activated protein kinase

Therapeutic angiogenesis has received much attention for its potential benefits in ischemic vascular disorders. Recently, the clinical application of hepatocyte growth factor (HGF) for therapeutic angiogenesis has become well known. Statins have also been reported to promote angiogenesis and ameliorate ischemic conditions. In the present study, we examined the effects of fluvastatin on HGF-induced angiogenesis using a human umbilical vein endothelial cell (HUVEC)/ normal human dermal fibroblast (NHDF) co-culture system. The HGF-induced angiogenesis was augmented by fluvastatin at low dose, but it was decreased at high dose. Although fluvastatin increased vascular endothelial growth factor expression in NHDFs, it was observed only at a high dose. Low-dose fluvastatin decreased the HGF-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation (Thr-180/ Tyr-182) and HUVEC apoptosis in the presence of HGF. SB203580, a p38 MAPK inhibitor, ameliorated anisomycin (a p38 MAPK activator)-induced angiogenesis suppression in the presence of HGF. Moreover, the augmentation of the HGF-induced angiogenesis by fluvastatin was abrogated by the p38 MAPK inhibitors, SB203580, SB202190, and FR167653. High-dose fluvastatin decreased Akt phosphorylation (Ser-473) and HUVEC proliferation, and it increased p27^kip1 in HUVECs. Interestingly, fluvastatin decreased the mRNA expression of integrins and tissue inhibitor of metalloproteinases (TIMPs) in HUVECs. Our data therefore indicate that the stimulatory effects of low-dose fluvastatin on the HGF-induced angiogenesis are mediated by its inhibitory effects on p38 MAPK phosphorylation induced by HGF, which may result in the suppression of EC apoptosis. High-dose fluvastatin inhibits Akt phosphorylation and HUVEC proliferation, and it increases p27^kip1, which may result in its inhibitory effects on angiogenesis. In addition, integrins and TIMPs are candidates for angiogenesis regulation by fluvastatin.