Published ahead of print on March 11, 2004, doi:10.1165/rcmb.2003-0397OC
© 2004 American Thoracic Society DOI: 10.1165/rcmb.2003-0397OC p42/44 Mitogen-Activated Protein Kinase Regulated by p53 and Nitric Oxide in Human Pulmonary Arterial Smooth Muscle CellsThird Department of Internal Medicine, and Department of Fundamental Nursing, University of Fukui, Fukui, Japan Address correspondence to: Shiro Mizuno M.D., Third Department of Internal Medicine, University of Fukui, 23-3 Matsuoka-cho Yoshida-gun, Fukui, Japan. E-mail: shirotan{at}qf6.so-net.ne.jp Although nitric oxide (NO) is known to inhibit vascular smooth muscle cell proliferation, the subcellular molecular mechanisms involved with the inhibitory signal transduction pathways are uncertain. We investigated the effect of exogenous NO on cell proliferation and the expression of p53, p21, and phosphorylated p42/44 mitogen-activated protein kinase (MAPK) in human pulmonary arterial smooth muscle cells (HPASMC). Both S-nitroso-N-acetyl penicillamine and diethylenetriaminelNONOate dose-dependently suppressed [3H]-thymidine incorporation in cultured HPASMC, and induced the expression of p53 and p21 protein. Further, the NO donors transiently increased the phosphorylation of p42/44 MAPK and then suppressed it. Although MAPK kinase inhibitors suppressed [3H]-thymidine incorporation by the cells, no significant change was observed in the expression of p53 and p21. The NO donors also suppressed the activation of p42/44 MAPK evoked by transient transfection of the wild-type p53 gene; however, they failed to suppress the activation of p42/44 MAPK in constitutive-active mutations of the Ras or Raf genes trasnsfected from HPASMC. These results indicate that exogenous NO is able to transiently activate p42/44 MAPK via the induction of p53, and then suppress it via inactivation of the Ras and Raf cascades.
Abbreviations: cyclin-dependent protein kinase, CDK • 2-(4-carboxy-phenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, cPTIO • diethylenetriaminelNONOate, DETANO • Dulbecco's modified Eagle's medium, DMEM • extracellular-regulated kinase1/2, ERK1/2 • fetal bovine serum, FBS • human pulmonary arterial smooth muscle cells, HPASMC • mitogen-activated protein kinase, MAPK • nitric oxide, NO • NO synthase, NOS • phosphate-buffered saline, PBS • polymerase chain reaction, PCR • smooth muscle cells, SMC • S-nitroso-N-acetyl penicillamine, SNAP • vascular smooth muscle cells, VSMC This article has been cited by other articles:
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