Glycated serum albumin-induced vascular smooth muscle cell proliferation through activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by protein kinase C

Biochem Biophys Res Commun. 2001 Mar 9;281(4):891-6. doi: 10.1006/bbrc.2001.4436.

Abstract

Proliferation of vascular smooth muscle cells (VSMC) contributes to the pathogenesis of atherosclerosis, and glycated serum albumin (GSA, Amadori adduct of albumin) might be a mitogen for VSMC proliferation, which may further be associated with diabetic vascular complications. In this study, we investigated the involvement of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and protein kinase C (PKC), in GSA-stimulated mitogenesis, as well as the functional relationship between these factors. VSMC stimulation with GSA resulted in a marked activation of ERK. The MAPK kinase (MEK) inhibitor, PD98059, blocked GSA-stimulated MAPK activation and resulted in an inhibition of GSA-stimulated VSMC proliferation. GSA also increased PKC activity in VSMC in a dose-dependent manner. The inhibition of PKC by the PKC inhibitors, GF109203X and Rottlerin (PKCdelta specific inhibitor), as well as PKC downregulation by phorbol 12-myristate 13-acetate (PMA), inhibited GSA-induced cell proliferation and blocked ERK activation. This indicates that phorbol ester-sensitive PKC isoforms including PKCdelta are involved in MAPK activation. Thus, we show that the MAPK cascade is required for GSA-induced proliferation, and that phorbol ester-sensitive PKC isoforms contribute to cell activation and proliferation in GSA-stimulated VSMC.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / drug effects*
  • Cell Line
  • DNA / biosynthesis
  • DNA / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Humans
  • Indoles / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • MAP Kinase Signaling System / drug effects
  • Maleimides / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / enzymology
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Serum Albumin / pharmacology*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcriptional Activation / drug effects

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Indoles
  • Isoenzymes
  • Maleimides
  • Recombinant Fusion Proteins
  • Serum Albumin
  • glycosylated serum albumin
  • DNA
  • Luciferases
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • bisindolylmaleimide I
  • Tetradecanoylphorbol Acetate
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one