An anti-ulcer drug, geranylgeranylacetone, suppresses inducible nitric oxide synthase in cultured vascular smooth muscle cells
An anti-ulcer drug, geranylgeranylacetone, suppresses inducible nitric oxide synthase in cultured vascular smooth muscle cells
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DOI：
10.1097/01.hjh.0000182525.74934.c0
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发表时间：
2005-10
影响因子：
4.9
通讯作者：
Keiji Yamamoto;M. Sarukawa;Takayuki Ito;H. Aoki;M. Ichida;K. Shimada
中科院分区：
文献类型：
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作者：
Keiji Yamamoto;M. Sarukawa;Takayuki Ito;H. Aoki;M. Ichida;K. Shimada
Objective Geranylgeranylacetone (GGA) is commonly used as an anti-ulcer drug.如果 GGA 影响血管组织中的诱导型一氧化氮合酶 (iNOS)，则可能会影响冠状动脉的疾病进展。我们研究了抗溃疡药物 GGA 对血管平滑肌细胞 iNOS 活性的影响。方法 我们用 Griess 试剂测量了培养的大鼠血管平滑肌细胞中亚硝酸盐（一氧化氮的稳定代谢物）的产生量。分别通过蛋白质印迹法和RNA印迹法测定iNOS蛋白和mRNA表达。通过凝胶阻滞测定分析核提取物中核因子（NF）-κB 蛋白的水平。通过蛋白质印迹法评估热休克蛋白 70（一种细胞保护分子）。结果 将培养物与 IL-1β 一起孵育 24 小时导致亚硝酸盐生成显着增加。 GGA 以剂量依赖性方式显着抑制血管平滑肌细胞白介素 1β 诱导的亚硝酸盐产生。 GGA 抑制亚硝酸盐的产生伴随着 iNOS mRNA 和蛋白质积累的减少。 GGA 本身并不调节亚硝酸盐产生的基础水平。 Interleukin-1β 诱导血管平滑肌细胞中 NF-κB 活化，而 GGA 的添加进一步抑制了这种 NF-κB 活化。 GGA本身以剂量依赖性方式诱导热休克蛋白70表达。结论 这些结果表明，GGA 部分通过抑制 NF-κB 活化来抑制细胞因子刺激的培养血管平滑肌细胞中 iNOS 的表达，表明 GGA 可能调节包括动脉粥样硬化在内的心血管疾病的病理生理学。此外，这种效应可能与 GGA 产生的热休克蛋白 70 有关。
Objective Geranylgeranylacetone (GGA) is commonly used as an anti-ulcer drug. If GGA affects inducible nitric oxide synthase (iNOS) in the vascular tissue, it could influence disease progression in coronary arteries. We investigated the effects of the anti-ulcer drug GGA on iNOS activity in vascular smooth muscle cells. Methods We measured the production of nitrite, a stable metabolite of nitric oxide, in cultured rat vascular smooth muscle cells with the Griess reagent. iNOS protein and mRNA expressions were assayed by western blotting and northern blotting, respectively. The levels of nuclear factor (NF)-κB proteins in nuclear extracts were analyzed by gel retardation assay. Heat shock protein 70, a cytoprotective molecule, was evaluated by western blotting. Results Incubation of cultures with interleukin-1β for 24 h caused a significant increase in nitrite generation. Interleukin-1β-induced nitrite production by vascular smooth muscle cells was significantly suppressed by GGA in a dose-dependent manner. GGA-suppressed nitrite production was accompanied by decreased iNOS mRNA and protein accumulations. GGA by itself did not modulate the basal level of nitrite production. Interleukin-1β induced NF-κB activation in vascular smooth muscle cells, and the addition of GGA further inhibited this NF-κB activation. GGA itself induced heat shock protein 70 expression in a dose-dependent manner. Conclusion These findings demonstrated that GGA suppresses iNOS expression in cytokine-stimulated cultured vascular smooth muscle cells partially through the suppression of NF-κB activation, suggesting that GGA may modulate the pathophysiology of cardiovascular diseases including atherosclerosis. In addition, this effect may be associated with heat shock protein 70 production by GGA.