Published ahead of print on March 11, 2004, doi:10.1165/rcmb.2003-0397OC Am. J. Respir. Cell Mol. Biol., Volume 31, Number 2, August 2004, 184-192 A more recent version of this article appeared on August 1, 2004
Submitted on November 10, 2003 p42/44 MAPK regulated by p53 and nitric oxide in human pulmonary arterial smooth muscle cellsShiro Mizuno1*,1 Third Department of Internal Medicine, University of Fukui, Fukui, Japan, 2 Department of Fundamental Nursing, University of Fukui, Fukui, Japan * To whom correspondence should be addressed. 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 MAPK in human pulmonary arterial smooth muscle cells (HPASMC). Both S-nitroso-N-acetyl penicillamine (SNAP) and diethylenetriaminelNONOate (DETANO) 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]- hymidine 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.
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