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(Hypertension. 2006;47:252.)
© 2006 American Heart Association, Inc.

Original Articles

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

From the Diabetes Center (S.C., Y.Q.) and Department of Medicine (D.G.G.), University of California at San Francisco.

Correspondence to David G. Gardner, Diabetes Center, 1109 HSW, University of California at San Francisco, San Francisco, CA 94143-0540. E-mail gardner{at}itsa.ucsf.edu

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 [³H]-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 [³H]-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 [³H]-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.

Key Words: muscle, smooth, vascular • endothelin • signal transduction

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