Inhibition of platelet-derived growth factor-induced mitogenesis by phosphodiesterase 3 inhibitors: role of protein kinase A in vascular smooth muscle cell mitogenesis

Biochem Pharmacol. 2000 Aug 1;60(3):381-7. doi: 10.1016/s0006-2952(00)00328-2.


Proliferation of vascular smooth muscle cells (SMC) in response to platelet-derived growth factor (PDGF) and other mitogens plays an important role in restenosis following coronary angioplasty. Elevation of adenosine 3',5'-cyclic monophosphate (cAMP) concentration in SMC has been shown to inhibit SMC mitogenesis and could be obtained either directly by stimulation of adenylyl cyclase-coupled receptors or indirectly by inhibition of cAMP-specific phosphodiesterase (PDE4) or the cyclic guanosine 3', 5'-monophosphate-inhibitable phosphodiesterase (PDE3). This study compared the effects of the selective PDE3 inhibitors trequinsin and quazinone with the selective PDE4 inhibitors Ro 20-1724 and rolipram on PDGF-induced DNA synthesis, mitogen-activated protein (MAP) kinase activation, cAMP levels, and protein kinase A (PKA) activation in SMC. Both PDE3 and PDE4 inhibitors stimulated intracellular PKA activation as seen from phosphorylation of vasodilator-stimulated phosphoprotein (VASP). However, only PDE3 inhibitors, and not inhibitors of PDE4, reduced PDGF-induced DNA synthesis and inhibited p42/p44 MAP kinase phosphorylation. At antimitogenic concentrations, the PDE3 inhibitors had only minor effects on cAMP levels. In contrast, PDE4 inhibitors increased the forskolin-induced cellular cAMP concentration 13- to 17-fold above control. These data demonstrate that inhibitors of PDE3 are potent antimitogenic agents and that a general increase in cellular cAMP levels and PKA activation per se are not sufficient to inhibit PDGF-induced SMC mitogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Animals
  • Cattle
  • Cell Adhesion Molecules / metabolism
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • DNA / biosynthesis
  • DNA / drug effects
  • Microfilament Proteins
  • Mitogen-Activated Protein Kinases / metabolism
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects*
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Platelet-Derived Growth Factor / antagonists & inhibitors
  • Platelet-Derived Growth Factor / physiology*
  • Thymidine / metabolism
  • Tritium


  • Cell Adhesion Molecules
  • Microfilament Proteins
  • Phosphodiesterase Inhibitors
  • Phosphoproteins
  • Platelet-Derived Growth Factor
  • vasodilator-stimulated phosphoprotein
  • Tritium
  • DNA
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Thymidine