Pravastatin-induced proangiogenic effects depend upon extracellular FGF-2.
Bottom Line: Here, we hypothesized that FGF-2 contributes to the proangiogenic effect of statins.We found that pravastatin, a hydrophilic statin, induced phosphorylation of the FGF receptor (FGFR) in human umbilical vein endothelial cells.These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular FGF-2.
Affiliation: Department of Pharmacology, Osaka City University Medical School, Osaka, Japan. email@example.comShow MeSH
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Mentions: The stimulation of FGFR by pravastatin involves the sequential activation of ERK1,2 and Akt. To determine whether the activation of the MAPK and PI3K/Akt pathways by pravastatin depends on FGFR phosphorylation, quiescent HUVECs were stimulated with pravastatin in the absence or the presence of SU5402 (10 μM), the FGFR tyrosine kinase inhibitor. Pravastatin induced ERK1,2 activation at 10 min., whereas pretreatment of ECs with SU5402 completely inhibited pravastatin-induced ERK1,2 phosphorylation (Fig. 4A). Preincubation of ECs with SU5402 alone did not affect the activation of ERK1,2. Likewise, evaluation of the effects of FGFR on Akt activation demonstrated that pravastatin-induced phosphorylation of Akt was suppressed by SU5402 (Fig. 4B). Next, we examined the participation of FGF-2 in FGFR activation by blocking extracellular FGF-2. The effects of FGF-2 on ERK1,2 and Akt activation was suppressed by FGF-2 antibody. Preincubation of ECs with FGF-2-neutralizing antibody (5 μg/ml) for 1 hr showed that the phosphorylation of ERK1,2 and Akt induced by pravastatin was comparable to that suppressed by SU5402 (Fig. 5A and B). Preincubation of ECs with SU5402 or FGF-2 antibody did not affect ERK1,2 and Akt phosphorylation. Thus, we found that the FGF-2/FGFR system contributes to pravastatin-induced ERK1,2 and Akt activation.
Affiliation: Department of Pharmacology, Osaka City University Medical School, Osaka, Japan. firstname.lastname@example.org