Regulation of serotonin-induced DNA synthesis of bovine pulmonary artery smooth muscle cells.
We have previously reported that serotonin [5-hydroxytryptamine (5-HT)] stimulates DNA synthesis of bovine pulmonary artery smooth muscle cells (SMC) by its high-affinity uptake. Uptake inhibitors, but not selective 5-HT receptor antagonists, prevented the stimulatory effect (S.-L. Lee and B. L. Fanburg. J. Cell. Physiol. 150:396-405, 1992). We have now further evaluated the mechanism by which 5-HT enhances SMC DNA synthesis. Although some serotonergic agonists mimicked this stimulation, selective 5-HT receptor agonists produced no or only minor and variable stimulatory effects. The action of 5-HT was not inhibited by inhibitors of phospholipases C and A2, the protein kinase C (PKC) inhibitors dihydrosphingosine and 1-(-isoquinolinylsulfonyl)-2 methylpiperazine (H-7), or down-regulation of PKC with phorbol 12,13-dibutyrate. Staurosporine, a reputed PKC and tyrosine kinase (TK) inhibitor, and genistein, a selective TK inhibitor, reversed the stimulatory effect of 5-HT in a dose-dependent manner. Before stimulation of thymidine incorporation into cellular DNA, 5-HT elevated c-myc and actin mRNAs. Imipramine, fluoxetine, staurosporine, and cholera toxin inhibited the stimulations of both DNA synthesis and c-myc and actin mRNA expressions by 5-HT. Thus the data support a concept that 5-HT-induced thymidine incorporation by SMC involves membrane transport of 5-HT that initiates tyrosine phosphorylation.
Lee
S L
SL
Department of Medicine, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111.
Wang
W W
WW
Lanzillo
J J
JJ
Fanburg
B L
BL
D000199:Actins / Q000235:genetics; D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis*; D019204:GTP-Binding Proteins / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology* / Q000502:physiology; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism
D000199:Actins; D012333:RNA, Messenger; D012701:Serotonin; D004247:DNA; D019204:GTP-Binding Proteins; D013936:Thymidine