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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Proliferation of Adult Rat Hepatocytes by Hepatocyte Growth Factor Is Potentiated by Both Phenylephrine and Metaproterenol

Mitsutoshi Kimura and Masahiko Ogihara
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1146-1154;
Mitsutoshi Kimura
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Masahiko Ogihara
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Abstract

We investigated whether or not beta and alphaadrenergic agonists could affect proliferation of adult rat hepatocytes induced by hepatocyte growth factor (HGF) during the early and late phases of primary culture. Adult rat hepatocytes underwent significant DNA synthesis after culture with 5 ng/ml HGF for 3 h at a low cell density (3.3 × 104cells/cm2). Under these culture conditions, the number of nuclei increased significantly during a subsequent 4-h culture period. Hepatocyte DNA synthesis and proliferation induced by 5 ng/ml HGF was reduced at high cell densities near confluence. Abeta adrenergic agonist, metaproterenol (10−7 M), and dibutyryl cAMP significantly potentiated hepatocyte DNA synthesis and proliferation at a concentration as low as 10−7 M when cultured in combination with 5 ng/ml HGF. Similarly, analpha-1 adrenergic agonist, phenylephrine (10−6–10−4 M) markedly potentiated HGF-induced hepatocyte DNA synthesis and proliferation. The phenylephrine effect was mimicked by a phorbol ester (10−6 M), but not by ionomycin (10−6 M). The mitogenic effects of HGF were almost completely blocked by simultaneous treatment of hepatocytes with genistein (5 × 10−6 M), U-73122 (10−6 M), wortmannin (10−7 M), sphingosine (3 × 10−6 M) and rapamycin (10 ng/ml). These results demonstrate that HGF can rapidly induce proliferation of adult rat hepatocytes in primary culture. However, this effect is dependent on the initial plating density. The co-mitogenic effects of metaproterenol and phenylephrine may involve both protein kinase A and protein kinase C activation, respectively. The results also suggest that following stimulation with HGF, activation of tyrosine kinase, phosphatidylinositol 3-kinase, phospholipase C and p70 ribosomal protein S6 kinase is essential for hepatocyte proliferation.

Footnotes

  • Send reprint requests to: Masahiko Ogihara, Ph. D., Biochemical Pharmacology Group, Faculty of Pharmaceutical Sciences, Josai University. 1–1, Keyakidai, Sakado, Saitama 350–02 Japan.

  • Abbreviations:
    HGF
    hepatocyte growth factor
    EGF
    epidermal growth factor
    DNA
    deoxyribonucleic acid
    PI(3)K
    phosphatidylinositol 3-kinase
    p70 S6K
    P70 ribosomal protein S6 kinase
    cAMP
    adenosine 3′,5′-cyclic monophosphate
    UK-14304
    5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline
    U-73122
    (1-[-[[17β-3-methoxyestra-1, 3, 5 (10)-triene-17-yl] amino] hexyl]-1H pyrrol-2, 5-dione)
    db-cAMP
    N6,2′-o-dibutyryl cAMP
    H-89
    N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide
    PKA
    protein kinase A
    PKC
    protein kinase C
    PLC
    phospholipase C
    DG
    1, 2-diacylglycerol
    IP3
    inositol 1,4,5-trisphosphate
    PMA
    phorbol myristate acetate
    PDGF
    platelet-derived growth factor
    HEPES
    N-[2-hydroxy-ethyl]-piperazine-N′-[2-ethane sulfonic acid]
    • Received February 12, 1997.
    • Accepted May 1, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Proliferation of Adult Rat Hepatocytes by Hepatocyte Growth Factor Is Potentiated by Both Phenylephrine and Metaproterenol

Mitsutoshi Kimura and Masahiko Ogihara
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1146-1154;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Proliferation of Adult Rat Hepatocytes by Hepatocyte Growth Factor Is Potentiated by Both Phenylephrine and Metaproterenol

Mitsutoshi Kimura and Masahiko Ogihara
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1146-1154;
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