High-glucose-induced nuclear factor κB activation in vascular smooth muscle cells

被引:94
作者
Hattori, Y [1 ]
Hattori, S [1 ]
Sato, N [1 ]
Kasai, K [1 ]
机构
[1] Dokkyo Univ, Sch Med, Dept Endocrinol, Mibu, Tochigi 3210293, Japan
关键词
vascular smooth muscle cells; nuclear factor kappa B; high glucose; glutathione; protein kinase C;
D O I
10.1016/S0008-6363(99)00425-3
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: Vascular smooth muscle cell (VSMC) dysfunction plays a role in diabetic macrovasculopathy. This dysfunction may be caused or exacerbated by expression of many of genes potently activated by the transcriptional factor nuclear factor kappa B (NF-kappa B). We have examined whether culture of VSMCs under high glucose conditions to stimulate the diabetic state can lead to the activation of NF-kappa B. Methods: NF-kappa B activation was assessed in VSMCs stably transfected with a cis-reporter plasmid containing the NF-kappa B binding sites. Results: Within 3-h incubation, high glucose (27.5 or 55 mmol/l) alone induced an increase in NF-kappa B activity in VSMCs; this increase was mimicked by mannitol given to deliver the same osmolar stress to the cells. High glucose or mannitol also enhanced TNF alpha-stimulated NF-kappa B activity. Incubation with high glucose for 48 h followed by stimulation with TNF alpha led to a marked potentiation of NF-kappa B activation compared with normoglycemic (5.5 mmol/l) VSMCs exposed to TNF alpha. while mannitol attenuated this effect. A 48-h incubation with high glucose substantially reduced glutathione (GSH) levels compared with normoglycemic VSMCs, whereas mannitol significantly increased GSH levels. An antioxidant N-acetyl-L-cysteine and a selective protein kinase C (PKC) inhibitor GF109203X significantly suppressed the TNF alpha-induced NF-kappa B activation, and abrogated potentiation of TNF alpha-induced NF-kappa B activity caused by high glucose (27.5 mmol/l). Conclusion: These results suggest that acutely high glucose causes alterations in osmolarity leading to activation of NF-kappa B, but that exposure to high glucose for more prolonged times causes changes in antioxidant defences and activation of PKC, which potentiates cytokine activation of NF-kappa B. Further definition of these pathways will help to delineate important signals mediating the aberrant behavior of VSMCs under hyperglycemic/diabetic conditions. (C) 2000 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:188 / 197
页数:10
相关论文
共 31 条
[1]   Mechanisms of disease - Nuclear factor-kappa b - A pivotal transcription factor in chronic inflammatory diseases [J].
Barnes, PJ ;
Larin, M .
NEW ENGLAND JOURNAL OF MEDICINE, 1997, 336 (15) :1066-1071
[2]   ROLE OF OXIDATIVE STRESS IN DEVELOPMENT OF COMPLICATIONS IN DIABETES [J].
BAYNES, JW .
DIABETES, 1991, 40 (04) :405-412
[3]   THE I-KAPPA-B PROTEINS - MULTIFUNCTIONAL REGULATORS OF REL/NF-KAPPA-B TRANSCRIPTION FACTORS [J].
BEG, AA ;
BALDWIN, AS .
GENES & DEVELOPMENT, 1993, 7 (11) :2064-2070
[4]   Advanced glycation end product-induced activation of NF-kappa B is suppressed by alpha-lipoic acid in cultured endothelial cells [J].
Bierhaus, A ;
Chevion, S ;
Chevion, M ;
Hofmann, M ;
Quehenberger, P ;
Illmer, T ;
Luther, T ;
Berentshtein, E ;
Tritschler, H ;
Muller, M ;
Wahl, P ;
Ziegler, R ;
Nawroth, PP .
DIABETES, 1997, 46 (09) :1481-1490
[5]  
BOURCIER T, 1987, BIOCHEM J, V245, P243
[6]   SMOOTH-MUSCLE CELL IN CULTURE [J].
CHAMLEYCAMPBELL, J ;
CAMPBELL, GR ;
ROSS, R .
PHYSIOLOGICAL REVIEWS, 1979, 59 (01) :1-61
[7]   GLUTATHIONE AND ITS REDOX SYSTEM IN DIABETIC POLYMORPHONUCLEAR LEUKOCYTES [J].
CHARI, SN ;
NATH, N ;
RATHI, AB .
AMERICAN JOURNAL OF THE MEDICAL SCIENCES, 1984, 287 (03) :14-15
[8]   VASCULAR THROMBOSIS IN TYPE-II DIABETES-MELLITUS [J].
COLWELL, JA .
DIABETES, 1993, 42 (01) :8-11
[9]   ACTIVATION OF PROTEIN-KINASE-C IN GLOMERULAR CELLS IN DIABETES - MECHANISMS AND POTENTIAL LINKS TO THE PATHOGENESIS OF DIABETIC GLOMERULOPATHY [J].
DERUBERTIS, FR ;
CRAVEN, PA .
DIABETES, 1994, 43 (01) :1-8
[10]   More cellular signals for atherogenesis? [J].
Edgington, T .
CIRCULATION, 1998, 98 (12) :1151-1152