Inhibition of platelet-derived growth factor-induced mitogenesis by phosphodiesterase 3 inhibitors: role of protein kinase A in vascular smooth muscle cell mitogenesis.
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.
Osinski
M T
MT
Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
Schrör
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D008840:Microfilament Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010726:Phosphodiesterase Inhibitors; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D000098662:Vasodilator-Stimulated Phosphoprotein; D014316:Tritium; D004247:DNA; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D013936:Thymidine