Fluvastatin upregulates inducible nitric oxide synthase expression in cytokine-stimulated vascular smooth muscle cells

被引:48
作者
Chen, H
Ikeda, U [1 ]
Shimpo, M
Ikeda, M
Minota, S
Shimada, K
机构
[1] Jichi Med Sch, Dept Cardiol, Minami Kawachi, Tochigi 3290498, Japan
[2] Jichi Med Sch, Dept Clin Immunol, Minami Kawachi, Tochigi 3290498, Japan
[3] Utsunomiya Univ, Hlth Sci Ctr, Utsunomiya, Tochigi, Japan
关键词
nitric oxide; atherosclerosis; interleukins; muscle; smooth;
D O I
10.1161/01.HYP.36.6.923
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Nitric oxide (NO) production by inducible NO synthase (iNOS) may play an important role in the pathogenesis of atherosclerosis. Although fluvastatin has been shown to reduce progression of atherosclerosis, it is not known whether it regulates iNOS expression. We investigated the effects of fluvastatin on iNOS expression and subsequent NO synthesis in vascular smooth muscle cells (VSMCs) and the mechanism by which fluvastatin exerts its effects. Fluvastatin significantly increased interleukin-1 beta (IL-1 beta)-induced nitrite production by VSMCs in a time-dependent (0 to 24 hours) and dose-dependent (10(-8) to 10(-5) mol/L) manner. Increased nitrite production by fluvastatin was accompanied by increased iNOS mRNA and protein accumulation. IL-1 beta induced nuclear factor-kappaB activation in VSMCs, which was not affected by fluvastatin. Exogenous mevalonate significantly prevented the stimulatory effect of fluvastatin on nitrite production. Cotreatment with geranylgeranyl-pyrophosphate also reversed the effect of fluvastatin. Furthermore, both Rho inhibitor C3 exoenzyme and Rho kinase inhibitor Y-27632 significantly increased IL-1 beta -induced nitrite accumulation in VSMCs, These results demonstrated that fluvastatin upregulates iNOS expression and subsequent NO formation in rat VSMCs through inhibition of Rho.
引用
收藏
页码:923 / 928
页数:6
相关论文
共 29 条
  • [1] Aji W, 1997, CIRCULATION, V95, P430
  • [2] Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase)
    Amano, M
    Ito, M
    Kimura, K
    Fukata, Y
    Chihara, K
    Nakano, T
    Matsuura, Y
    Kaibuchi, K
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (34) : 20246 - 20249
  • [3] Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy
    Ballantyne, CM
    Herd, JA
    Ferlic, LL
    Dunn, JK
    Farmer, JA
    Jones, PH
    Schein, JR
    Gotto, AM
    [J]. CIRCULATION, 1999, 99 (06) : 736 - 743
  • [4] Distribution and prevalence of inducible nitric oxide synthase in atherosclerotic vessels of long-term cholesterol-fed rabbits
    Behr, D
    Rupin, A
    Fabiani, JN
    Verbeuren, TJ
    [J]. ATHEROSCLEROSIS, 1999, 142 (02) : 335 - 344
  • [5] The L-arginine-nitric oxide pathway: Role in atherosclerosis and therapeutic implications
    Boger, RH
    BodeBoger, SM
    Frolich, JC
    [J]. ATHEROSCLEROSIS, 1996, 127 (01) : 1 - 11
  • [6] Lovastatin maintains nitric oxide -: but not EDHF-mediated endothelium-dependent relaxation in the hypercholesterolemic rabbit carotid artery
    Brandes, RP
    Behra, A
    Lebherz, C
    Böger, RH
    Bode-Böger, SM
    Mügge, A
    [J]. ATHEROSCLEROSIS, 1999, 142 (01) : 97 - 104
  • [7] Inhibition of protein geranylgeranylation causes a superinduction of nitric-oxide synthase-2 by interleukin-1 beta in vascular smooth muscle cells
    Finder, JD
    Litz, JL
    Blaskovich, MA
    McGuire, TF
    Qian, YM
    Hamilton, AD
    Davies, P
    Sebti, SM
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (21) : 13484 - 13488
  • [8] REGULATION OF THE MEVALONATE PATHWAY
    GOLDSTEIN, JL
    BROWN, MS
    [J]. NATURE, 1990, 343 (6257) : 425 - 430
  • [9] 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture
    Guijarro, C
    Blanco-Colio, LM
    Ortego, M
    Alonso, C
    Ortiz, A
    Plaza, JJ
    Diaz, C
    Hernandez, G
    Egido, J
    [J]. CIRCULATION RESEARCH, 1998, 83 (05) : 490 - 500
  • [10] Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells
    Hernández-Perera, O
    Pérez-Sala, D
    Navarro-Antolín, J
    Sánchez-Pascuala, R
    Hernández, G
    Díaz, C
    Lamas, S
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (12) : 2711 - 2719