Biphasic Effect of HMG-CoA Reductase Inhibitor, Pitavastatin, on Vascular Endothelial Cells and Angiogenesis

Masayuki Katsumoto; Tetsuji Shingu; Rieko Kuwashima; Atsunori Nakata; Shuichi Nomura; Kazuaki Chayama

doi:10.1253/circj.69.1547

Experimental Investigation

Biphasic Effect of HMG-CoA Reductase Inhibitor, Pitavastatin, on Vascular Endothelial Cells and Angiogenesis

Masayuki Katsumoto, Tetsuji Shingu, Rieko Kuwashima, Atsunori Nakata, Shuichi Nomura, Kazuaki Chayama

Author information

Masayuki Katsumoto
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University
Tetsuji Shingu
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University
Rieko Kuwashima
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University
Atsunori Nakata
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University
Shuichi Nomura
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University
Kazuaki Chayama
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University

Keywords: Angiogenesis, Isoprenoids, Migration, Pitavastatin, Proliferation, Vascular endothelial cells

JOURNAL FREE ACCESS

2005 Volume 69 Issue 12 Pages 1547-1555

DOI https://doi.org/10.1253/circj.69.1547

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Abstract

Background HMG-CoA reductase inhibitors (statins) have pleiotropic effects beyond their cholesterol-lowering effect. However, consensus on the effect of statins on endothelial cells and angiogenesis has not yet been reached. Methods and Results The effects of pitavastatin on the migration, proliferation and viability of human epidermal microvessel endothelial cells (HMVECs) were examined using scratch assay, chemotaxis chamber, bromodeoxyuridine incorporation, trypan blue dye exclusion test, and nuclear DNA staining. Pitavastatin enhanced the migration, proliferation and viability of HMVECs at a low concentration (0.01 μmol/L) but inhibited them at high concentration (1 μmol/L). The inhibitory effect on cell viability by high concentration of pitavastatin was recovered by geranylgeranyl pyrophosphate, but the effect on migration and proliferation was not. The cell activating effect of a low concentration of pitavastatin was reversed by both farnesyl pyrophosphate and geranylgeranyl pyrophosphate. A quail chorioallantoic membrane assay showed that high concentration (1 μmol/L) of pitavastatin reduced fibroblast growth factor-2-induced angiogenesis, whereas low concentration (0.3 μmol/L) tended to increase angiogenesis. Conclusion Pitavastatin has a biphasic effect on HMVECs and on angiogenesis through at least 2 different pathways that include the mevalonate pathway. (Circ J 2005; 69: 1547 - 1555)

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