Tyrphostins inhibit PDGF-induced DNA synthesis and associated early events in smooth muscle cells.
Tyrphostins are low-molecular-weight synthetic inhibitors of protein tyrosine kinase, which block cell proliferation. Since platelet-derived growth factor (PDGF) is thought to figure prominently in disorders of vascular smooth muscle cells (VSMC), such as atherosclerosis, hypertension, and restenosis, we examined whether tyrphostins would inhibit PDGF-induced mitogenesis in VSMC. In this communication, we demonstrate that tyrphostins with the benzenemalononitrile nucleus inhibited PDGF-dependent growth of VSMC as well as PDGF-dependent DNA synthesis in these cells, with the concentrations for 50% inhibition ranging from 0.04 to 9 microM. Up to 30-fold higher tyrphostin concentrations were required to inhibit serum-stimulated DNA synthesis of VSMC. The effect of the tyrphostins is reversible, since on their removal a normal proliferative response to PDGF was resumed. Tyrphostins also inhibited PDGF-receptor autophosphorylation and PDGF-induced phosphorylation of intracellular substrates, including the phosphorylation of phospholipase C-gamma, with a potency ratio similar to their antimitogenic activity. The expression of c-fos mRNA, a mitogenic nuclear signal, was also reduced in PDGF-stimulated VSMC treated with tyrphostins at concentrations which inhibit PDGF-induced mitogenesis. It is concluded that tyrphostins are potent reversible inhibitors of PDGF-induced mitogenesis which act by inhibiting the tyrosine kinase activity of the PDGF receptor and the subsequent signaling cascade. Tyrphostins may be useful in the study and treatment of VSMC proliferation disorders.
Bilder
G E
GE
Department of Cardiovascular Biology, Rhône-Poulenc Rorer, King of Prussia, Pennsylvania 19406.
Krawiec
J A
JA
McVety
K
K
Gazit
A
A
Gilon
C
C
Lyall
R
R
Zilberstein
A
A
Levitzki
A
A
Perrone
M H
MH
Schreiber
A B
AB
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects*; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology; D017479:Receptors, Platelet-Derived Growth Factor; D013329:Structure-Activity Relationship; D014162:Transfection; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*
D002396:Catechols; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D010738:Type C Phospholipases