Pravastatin‐induced proangiogenic effects depend upon extracellular FGF‐2

Journal of Cellular and Molecular Medicine

Masayuki Shiota¹  Yuko Hikita¹  Yukiko Kawamoto¹  Hiromi Kusakabe¹  Masako Tanaka¹  Yasukatsu Izumi¹  Takafumi Nakao¹  Katsuyuki Miura³  Yoshihiko Funae² 

[1] Department of Pharmacology, Osaka City University Medical School, Osaka, Japan;Department of Chemical Biology, Osaka City University Medical School, Osaka, Japan;Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka, Japan

关键词: statin;    pleiotropic effect;    endothelial cells;    FGF‐2;   

DOI  :  10.1111/j.1582-4934.2011.01494.x

来源: Wiley

【 摘 要 】

Abstract

The HMG-CoA reductase inhibitors (statins) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile, and to induce angiogenesis. The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K/Akt pathway in endothelial cells; however, it is unclear how statins activate this pathway. Pravastatin-mediated activation of Akt and MAPK occurs rapidly (within 10 min.) and at low doses (10 nM). 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. SU5402, an inhibitor of FGFR, abolished pravastatin-induced PI3K/Akt and MAPK activity. Likewise, anti-FGF-2 function-blocking antibodies inhibited Akt and MAPK activity. Moreover, depletion of extracellular FGF-2 by heparin prevented pravastatin-induced phosphorylation of Akt and MAPK. Treatment with FGF-2 antibody inhibited pravastatin-enhanced endothelial cell proliferation, migration and tube formation. These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular FGF-2.

【 授权许可】

Unknown   
© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd