Signal transduction mechanism for potentiation by α1- and β2-adrenoceptor agonists of l-ascorbic acid-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes

• Published in: European journal of pharmacology Vol. 700; no. 1-3; pp. 2 - 12
• Main Authors: Moteki, Hajime, Kimura, Mitsutoshi, Sunaga, Katsuyoshi, Tsuda, Tadashi, Ogihara, Masahiko
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.01.2013
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Adrenergic alpha-1 Receptor Agonists - pharmacology; Adrenergic beta-2 Receptor Agonists - pharmacology; Animals; Ascorbic Acid - pharmacology; Cell Proliferation - drug effects; Cells, Cultured; Cross-talk; DNA - biosynthesis; Drug Synergism; Extracellular Signal-Regulated MAP Kinases - metabolism; Extracellular-signal regulated kinase (ERK); Hepatocyte; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; l-ascorbic acid; Male; Metaproterenol - pharmacology; Phenylephrine - pharmacology; Phosphorylation - drug effects; Rats; Rats, Wistar; Receptor, IGF Type 1 - metabolism; Receptors, Adrenergic, alpha-1 - metabolism; Receptors, Adrenergic, beta-2 - metabolism; Signal Transduction - drug effects; Tetradecanoylphorbol Acetate - pharmacology; Time Factors; α1-, α2- and β2-adrenoceptor agonist; l-ascorbic acid; Hepatocyte; Extracellular-signal regulated kinase (ERK); α1-, α2- and β2-adrenoceptor agonist; Cross-talk
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2012.12.010

We investigated the effects of α- and β-adrenoceptor agonists on l-ascorbic acid-induced hepatocyte DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. The results showed that phenylephrine (10−6M) and metaproterenol (10−6M) alone did not induce hepatocyte DNA synthesis and proliferation. However, when combined with l-ascorbic acid (10−6M), these adrenoceptor agonists potentiated the hepatocyte DNA synthesis and proliferation induced by l-ascorbic acid. Then intracellular signal transduction mechanisms for the effects of phenylephrine and metaproterenol on l-ascorbic acid-induced hepatocyte mitogenesis were examined. Western blot analysis showed that phenylephrine and metaproterenol did not potentiate l-ascorbic acid-induced insulin-like growth factor I receptor tyrosine kinase phosphorylation. In contrast, they both significantly potentiated l-ascorbic acid-induced extracellular-signal regulated kinase-2 (ERK2) phosphorylation within 5min. Moreover, cell-permeable second messenger analogs phorbol ester (10−7M) and 8-bromo cAMP (10−7M) mimicked the effects of phenylephrine and metaproterenol on l-ascorbic acid-induced ERK2 phosphorylation. The effects of these adrenoceptor agents were specifically antagonized by GF109203X and H-89, respectively. These results indicate that activation of ERK2 via protein kinas C and protein kinase A represents a mechanism for potentiation of l-ascorbic acid-induced hepatocyte DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.