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Compound K, an intestinal metabolite of ginsenosides, inhibits PDGF-BB-induced VSMC proliferation and migration through G1 arrest and attenuates neointimal hyperplasia after arterial injury

  • Eun-Seok Park
    Correspondence
    Corresponding author. Tel.: +82 43 8403587; fax: +82 43 8403872.
    Affiliations
    Department of Applied Biochemistry, Division of Life Science, College of Health and Biomedical Science, Konkuk University, 322 Danwol-dong, Chungju 380-701, Republic of Korea
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  • Kang pa Lee
    Affiliations
    Department of Physiology, Institute of Functional Genomics, School of Medicine, Konkuk University, 322 Danwol-dong, Choongju 380-701, Republic of Korea
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  • Seung Hyo Jung
    Affiliations
    Department of Physiology, Institute of Functional Genomics, School of Medicine, Konkuk University, 322 Danwol-dong, Choongju 380-701, Republic of Korea
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  • Dong-Youb Lee
    Affiliations
    Department of Physiology, Institute of Functional Genomics, School of Medicine, Konkuk University, 322 Danwol-dong, Choongju 380-701, Republic of Korea
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  • Kyung Jong Won
    Affiliations
    Department of Physiology, Institute of Functional Genomics, School of Medicine, Konkuk University, 322 Danwol-dong, Choongju 380-701, Republic of Korea
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  • Yeo-Pyo Yun
    Affiliations
    College of Pharmacy, Medical Research Center, Chungbuk National University, Cheongju 361-763, Republic of Korea
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  • Bokyung Kim
    Correspondence
    Corresponding author. Tel.: +82 43 8403726; fax: +82 43 8519329.
    Affiliations
    Department of Physiology, Institute of Functional Genomics, School of Medicine, Konkuk University, 322 Danwol-dong, Choongju 380-701, Republic of Korea
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      Abstract

      Objective

      Compound K (CK), an intestinal metabolite of ginsenosides, has pharmacological properties such as anti-angiogenesis, anti-inflammation, anti-platelet and anti-cancer activities. In the present study, we investigated the inhibitory effect of CK on vascular smooth muscle cell (VSMC) proliferation and migration in vitro and neointima formation in a rat carotid artery injury model.

      Results

      CK significantly inhibited both the proliferation and migration of PDGF-BB-stimulated VSMCs in a concentration-dependent manner. In accordance with these findings, CK blocked the PDGF-BB-induced progression of synchronized cells through the G0/G1 phase of the cell cycle. CK also decreased the expressions of cell cycle-related proteins, including cyclin-dependent kinase (CDK) 2, cyclin E, CDK4, cyclin D1, and proliferative cell nuclear antigen (PCNA) in response to PDGF. However, CK did not affect early signal transduction through PDGF-Rβ, Akt, ERK1/2 and PLC-γ1 phosphorylation. CK attenuated PDGF-BB-induced VSMC migration by inhibiting MMP-2 and MMP-9 expression. Furthermore, the CK-treated groups showed a significant reduction in neointima formation vs. the control group. Immunohistochemical staining demonstrated decreased expression of PCNA in the neointima of the CK-treated group.

      Conclusion

      Our findings demonstrated that CK was capable of suppressing the abnormal VSMC proliferation and migration. It suggested that CK can be a therapeutic agent to control pathologic cardiovascular conditions such as restenosis and atherosclerosis.

      Highlights

      • CK (compound K) prevents PDGF-BB-induced VSMC proliferation and migration.
      • CK inhibited cell cycle progression via cell cycle-related proteins.
      •  CK attenuated PDGF-BB-induced VSMC migration by inhibiting MMP-2 and -9 expression.
      • CK caused a significant reduction in neointimal hyperplasia.
      • CK may be useful for individuals with a high risk of cardiovascular diseases.

      Keywords

      Abbreviations:

      CDK (cyclin-dependent kinase), DMEM (Dulbecco's Modified Eagle's Media), DMSO (dimethylsulfoxide), ERK (extracellular signal regulated kinase), FBS (fetal bovine serum), HEPES (N-[2-hydroxyethyl]piperazine-N-[2-ethanesulfonic acid]), MAPK (mitogen-activated protein kinase), PBS (phosphate buffered saline), PDGF (platelet-derived growth factor), SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), VSMCs (vascular smooth muscle cells)
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