Pravastatin-induced proangiogenic effects depend upon extracellular FGF-2

Masayuki Shiota, Yuko Hikita, Yukiko Kawamoto, Hiromi Kusakabe, Masako Tanaka, Yasukatsu Izumi, Takafumi Nakao, Katsuyuki Miura, Yoshihiko Funae, Hiroshi Iwao

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2001-2009
Number of pages9
JournalJournal of Cellular and Molecular Medicine
Volume16
Issue number9
DOIs
Publication statusPublished - 2012 Sep
Externally publishedYes

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Pravastatin
Fibroblast Growth Factor 2
Fibroblast Growth Factor Receptors
Endothelial Cells
Phosphatidylinositol 3-Kinases
Phosphorylation
Blocking Antibodies
Human Umbilical Vein Endothelial Cells
Cell Movement
Heparin
Cholesterol
Cell Proliferation
Antibodies

Keywords

  • Endothelial cells
  • FGF-2
  • Pleiotropic effect
  • Statin

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

Cite this

Pravastatin-induced proangiogenic effects depend upon extracellular FGF-2. / Shiota, Masayuki; Hikita, Yuko; Kawamoto, Yukiko; Kusakabe, Hiromi; Tanaka, Masako; Izumi, Yasukatsu; Nakao, Takafumi; Miura, Katsuyuki; Funae, Yoshihiko; Iwao, Hiroshi.

In: Journal of Cellular and Molecular Medicine, Vol. 16, No. 9, 09.2012, p. 2001-2009.

Research output: Contribution to journalArticle

Shiota, M, Hikita, Y, Kawamoto, Y, Kusakabe, H, Tanaka, M, Izumi, Y, Nakao, T, Miura, K, Funae, Y & Iwao, H 2012, 'Pravastatin-induced proangiogenic effects depend upon extracellular FGF-2', Journal of Cellular and Molecular Medicine, vol. 16, no. 9, pp. 2001-2009. https://doi.org/10.1111/j.1582-4934.2011.01494.x
Shiota, Masayuki ; Hikita, Yuko ; Kawamoto, Yukiko ; Kusakabe, Hiromi ; Tanaka, Masako ; Izumi, Yasukatsu ; Nakao, Takafumi ; Miura, Katsuyuki ; Funae, Yoshihiko ; Iwao, Hiroshi. / Pravastatin-induced proangiogenic effects depend upon extracellular FGF-2. In: Journal of Cellular and Molecular Medicine. 2012 ; Vol. 16, No. 9. pp. 2001-2009.
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