Role of p42/p44 mitogen-activated-protein kinase and p21waf1/cip1 in the regulation of vascular smooth muscle cell proliferation by nitric oxide

被引:57
作者
Bauer, PM [1 ]
Buga, GM [1 ]
Ignarro, LJ [1 ]
机构
[1] Univ Calif Los Angeles, Sch Med, Dept Mol & Med Pharmacol, Ctr Hlth Sci, Los Angeles, CA 90095 USA
关键词
polyamines; ornithine decarboxylase; atherosclerosis; MAPK;
D O I
10.1073/pnas.211443198
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The purpose of this study was to determine the involvement of the p42/p44 mitogen-activated protein kinase (MAPK) pathway and induction of p21(waf1/cip1) in the antiproliferative effects of nitric oxide (NO) on rat aortic smooth muscle cells (RASMC). NO, like alpha -difluoromethylornithine (DFMO), interferes with cell proliferation by inhibiting ornithine decarboxylase (ODC) and, therefore, polyamine synthesis. S-nitroso-N-acetylpenicillamine or (Z)-1-[N(2-aminoethyl)-N-(2-aminoethyl)-amino]-diazen-1-ium-1,2-diolate inhibited RASMC growth at concentrations as low as 3 muM, and DFMO elicited effects at concentrations of 100 muM or greater. The cytostatic effect of NO and DFMO was prevented by the MAPK kinase 1/2 inhibitors PD 098,059 or U0126. This finding suggests that the p42/p44 MAPK pathway is involved in the inhibition of RASMC proliferation by NO. Western blot analysis revealed that treatment of RASMC with NO or DFMO leads to activation of p42/p44 MAPK and induction of p21(waf1/cip1). This effect was prevented by MAPK kinase 1/2 inhibitors, suggesting that induction of p21(waf1/cip1) depended on activation of p42/p44. Moreover, activation of p42/p44 and induction of p21(waf1/cip1) were prevented by exogenous putrescine but not ornithine, suggesting this effect was due to the inhibition of ODC by NO or DFMO. Finally, activation of p42/p44 MAPK and induction of p21(waf1/cip1) were cGMP-independent. Neither 1H-(1,2,4)oxadiazolo[4,3-alpha ]quinoxalin-1-one nor zaprinast influenced the cytostatic effect of NO or DFMO or their ability to activate these signal transduction pathways. These observations suggest that inhibition of ODC and accompanying putrescine production are the underlying mechanisms by which NO and DFMO activate the MAPK pathway to promote induction of p21(waf1/cip1) and consequent inhibition of cell proliferation.
引用
收藏
页码:12802 / 12807
页数:6
相关论文
共 37 条
  • [1] Nitric oxide inhibits ornithine decarboxylase by S-nitrosylation
    Bauer, PM
    Fukuto, JM
    Buga, GM
    Pegg, AE
    Ignarro, LJ
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 262 (02) : 355 - 358
  • [2] BAUER PM, 2001, IN PRESS J BIOL CHEM
  • [3] Sodium nitroprusside inhibits proliferation and putrescine synthesis in human colon carcinoma cells
    Blachier, F
    Robert, V
    Selamnia, M
    Mayeur, C
    Duee, PH
    [J]. FEBS LETTERS, 1996, 396 (2-3) : 315 - 318
  • [4] Buga G. M., 1998, AM J PHYSIOL, V275, P1256
  • [5] Cooke JP, 1998, J INVEST MED, V46, P377
  • [6] DEMEYER GRY, 1994, BRIT J PHARMACOL, V112, P471
  • [7] DEMEYER GRY, 2000, NITRIC OXIDE BIOL PA, P547
  • [8] INVOLVEMENT OF ORNITHINE DECARBOXYLASE IN THE CONTROL OF PROLIFERATION OF THE HT29 HUMAN COLON CANCER CELL-LINE - EFFECT OF VASOACTIVE-INTESTINAL-PEPTIDE ON ENZYME-ACTIVITY
    GAMET, L
    CAZENAVE, Y
    TROCHERIS, V
    DENISOUXVIEL, C
    MURAT, JC
    [J]. INTERNATIONAL JOURNAL OF CANCER, 1991, 47 (04) : 633 - 638
  • [9] NITRIC OXIDE-GENERATING VASODILATORS INHIBIT MITOGENESIS AND PROLIFERATION OF BALB/C3T3 FIBROBLASTS BY A CYCLIC GMP-INDEPENDENT MECHANISM
    GARG, UC
    HASSID, A
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1990, 171 (01) : 474 - 479
  • [10] INHIBITION OF RAT MESANGIAL CELL MITOGENESIS BY NITRIC OXIDE-GENERATING VASODILATORS
    GARG, UC
    HASSID, A
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1989, 257 (01): : F60 - F66