A Role for p38 Mitogen-Activated Protein Kinase and c-Myc in Endothelin-Dependent Rat Aortic Smooth Muscle Cell Proliferation

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Abstract
We have demonstrated recently that endothelin (ET) stimulates rat aortic smooth muscle cell proliferation through an extracellular signal–regulated kinase (ERK)–dependent mechanism. Approximately 70% of ET-dependent [ 3 H]-thymidine incorporation in these cells signals through this system. In the present study, we show that the residual mitogenic activity requires an intact p38 mitogen-activated protein kinase (p38 MAPK) system and increased c-myc gene expression. ET increased [ 3 H]-thymidine incorporation in rat aortic smooth muscle cells ≈5-fold. p38 MAPK inhibition with SB203580 or ERK/ERK kinase inhibition with PD98059 each effected ≈70% inhibition in ET-dependent DNA synthesis, whereas the combination led to nearly complete blockade of the ET effect. ET also increased c-myc RNA levels and c-Myc protein levels in these cells. The increment in c-Myc expression was blocked by SB203580 but not by PD98059. Use of antisense oligonucleotides directed against the translation start site of the c-myc transcript, but not scrambled oligonucleotide sequence, resulted in ≈60% decrease in ET-dependent [ 3 H]-thymidine incorporation. The combination of antisense c-myc and PD98059 resulted in near complete inhibition of ET-dependent DNA synthesis. Both ET and c-Myc increased expression and promoter activity of E2F, a transcription factor that has been linked to enhanced cell cycle activity. The ET-dependent increment in E2F promoter activity was suppressed after treatment with SB203580 or antisense c-myc but not by PD98059 or a scrambled oligonucleotide sequence. Collectively, these findings demonstrate that ET uses 2 complementary signal transduction cascades (ERK and p38 MAPK) to control proliferative activity of vascular smooth muscle cells.