Blockade of DNA synthesis induced by platelet-derived growth factor by tranilast, an inhibitor of calcium entry, in vascular smooth muscle cells.
The present study was conducted to establish a pharmacological method of controlling growth of vascular smooth muscle cells (VSMC) by blocking calcium entry. In cultured rat VSMC, 1 nM platelet-derived growth factor (PDGF) induced a biphasic elevation of cytoplasmic free calcium concentration, ([Ca2+]c). The second sustained phase of [Ca2+]c was dependent on extracellular calcium. At lower concentrations, PDGF induced oscillatory changes in [Ca2+]c, and reduction of extracellular calcium attenuated the oscillation. An antiallergic compound, tranilast, abolished the sustained phase of [Ca2+]c induced by 1 nM PDGF. Tranilast also inhibited the oscillatory changes in [Ca2+]c induced by 200 pM PDGF. In addition, PDGF-induced calcium influx in the late G1 phase, as assessed by measuring the initial uptake of 45Ca, was inhibited by tranilast in a concentration-dependent manner. Tranilast also inhibited PDGF-augmented DNA synthesis; the ID50 for the inhibition of DNA synthesis was nearly identical to that for calcium influx. Although tranilast blocked PDGF-induced calcium entry, it did not affect PDGF-mediated autophosphorylation of the PDGF receptor, activation of phosphatidylinositol 3-kinase, activation of Ras or mitogen-activated protein kinase. Similarly, PDGF-induced elevation of diacylglycerol was not affected by tranilast. These results suggest that the antiallergic drug tranilast inhibits PDGF-induced DNA synthesis by blocking PDGF-mediated calcium entry. Tranilast may be of use in controlling PDGF-induced DNA synthesis in VSMC.
Nie
L
L
Department of Cell Biology, Gunma University, Maebashi, Japan.
Mogami
H
H
Kanzaki
M
M
Shibata
H
H
Kojima
I
I
D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D010982:Platelet-Derived Growth Factor; D062367:ortho-Aminobenzoates; D004247:DNA; C012293:tranilast; D002118:Calcium