REGULATION OF SEROTONIN-INDUCED DNA-SYNTHESIS OF BOVINE PULMONARY-ARTERY SMOOTH-MUSCLE CELLS

Regulation of serotonin-induced DNA synthesis of bovine pulmonary arte ry smooth muscle cells. Am. J. Physiol. 266 (Lung Cell. Mol, Physiol. 10): L53-L60, 1994.-We have previously reported that serotonin [5-hydr oxytryptamine (5-HT)] stimulates DNA synthesis of bovine pulmonary art ery smooth muscle cells (SMC) by its high-affinity uptake. Uptake inhi bitors, but not selective 5-HT receptor antagonists, prevented the sti mulatory 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 mimic ked this stimulation, selective 5-HT receptor agonists produced no or only minor and variable stimulatory effects. The action of 5-HT was no t inhibited by inhibitors of phospholipases C and A(2), the protein ki nase C (PKC) inhibitors dihydrosphingosine and 1-(-isoquinolinylsulfon yl)-2 methylpiperazine (H-7), or down-regulation of PKC with phorbol 1 2,13-dibutyrate. Staurosporine, a reputed PKC and tyrosine kinase (TK) inhibitor, and genistein, a selective TK inhibitor, reversed the stim ulatory 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 m RNA expressions by 5-HT. Thus the data support a concept that 5-HT-ind uced thymidine incorporation by SMC involves membrane transport of 5-H T that initiates tyrosine phosphorylation.