Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, People's Republic of China.
Cardiovasc Res. 2010 Apr 1;86(1):141-50. doi: 10.1093/cvr/cvp388. Epub 2009 Dec 10.
High glucose promotes macrophage-derived foam cell formation involved in increased influx or reduced efflux of lipids. The aim of this study is to investigate the influence of hyperglycaemia on foam cell transformation of vascular smooth muscle cells (VSMCs) and possible mechanisms contributing to these effects.
The results showed that high glucose increased the expression of CD36, a regulator of lipid influx, and suppressed the expression and activity of the adenosine triphosphate-binding cassette (ABC) transporter ABCG1, a regulator of cholesterol efflux to high-density lipoprotein, in a dose- and time-dependent manner. However, cholesterol efflux to lipid-free apoAI was not impaired. VSMCs exposed to high glucose readily developed into lipid-loaded cells, as demonstrated by Oil Red O staining and cholesterol content analysis. In addition, high glucose-induced down-regulation of ABCG1 was reversed by nuclear factor-kappaB (NF-kappaB) inhibitors BAY 11-7085 and tosyl-phenylalanine chloromethyl ketone and by the antioxidant N-acetyl-L-cysteine (NAC). This reversal was accompanied by reduced cellular lipid content. Also, NAC and NF-kappaB inhibitors can effectively block the high glucose-induced activity of NF-kappaB binding to DNA and/or peroxide production.
These results suggested that hyperglycaemia-induced foam cell formation in VSMCs was related to the imbalanced lipid flux by increasing CD36-mediated modified low-density lipoprotein uptake and reducing ABCG1-regulated cellular cholesterol efflux. Moreover, this effect was associated with increased oxidative stress and activated NF-kappaB pathway signalling.
高血糖促进了巨噬细胞源性泡沫细胞的形成，涉及脂质内流增加或流出减少。本研究旨在探讨高血糖对血管平滑肌细胞（VSMCs）泡沫细胞转化的影响及其可能的作用机制。
结果表明，高葡萄糖以剂量和时间依赖的方式增加了脂质内流调节剂 CD36 的表达，同时抑制了胆固醇流出到高密度脂蛋白的三磷酸腺苷结合盒（ABC）转运体 ABCG1 的表达和活性。然而，胆固醇向无脂载脂蛋白 AI 的流出并未受损。暴露于高葡萄糖的 VSMCs 很容易发展成富含脂质的细胞，这可以通过油红 O 染色和胆固醇含量分析来证明。此外，高葡萄糖诱导的 ABCG1 下调可被核因子-κB（NF-κB）抑制剂 BAY 11-7085 和对甲苯磺酰基-L-苯丙氨酸氯甲基酮以及抗氧化剂 N-乙酰-L-半胱氨酸（NAC）逆转。这种逆转伴随着细胞脂质含量的减少。此外，NAC 和 NF-κB 抑制剂可有效阻断高葡萄糖诱导的 NF-κB 与 DNA 的结合活性和/或过氧化物的产生。
这些结果表明，高血糖诱导的 VSMCs 泡沫细胞形成与通过增加 CD36 介导的修饰性 LDL 摄取和减少 ABCG1 调节的细胞胆固醇流出导致的脂质通量失衡有关。此外，这种作用与氧化应激增加和激活 NF-κB 信号通路有关。
