硫化氢对动脉粥样硬化的影响及其与CX3CR1的关系  

Effect of Hydrogen Sulfide on the Development and Progression of Atherosclerosis with Respect to Chemokine Receptor CX3CR1 Expression in Plaques

作　　者：张阿莲[1] 高霖[1] 程纯[1] 王长谦[1] 张绘莉[1] 

机构地区：[1]上海交通大学医学院附属第九人民医院心内科,上海市200011

出　　处：《中国分子心脏病学杂志》2014年第1期839-844,共6页Molecular Cardiology of China

基　　金：上海科委浦江人才计划(09PJ1407000);国家自然科学基金青年基金(30900522);上海高校青年教师培养资助计划(jdy09058)

摘　　要：目的在高脂饮食ApoE基因敲除小鼠动脉粥样硬化模型中,探讨硫化氢对动脉粥样硬化斑块的影响及其与斑块内趋化因子受体CX3CR1的关系。方法 10周龄、雄性纯合子ApoE基因敲除小鼠予以高脂饮食喂养,在高脂饮食喂养第4、8、12、24周时处死小鼠并留取血浆和主动脉,通过化学比色法和Western Blot技术检测血浆硫化氢水平和主动脉胱硫醚-γ-裂解酶(CSE)表达情况。一部分小鼠在高脂饮食4或12周后开始每天予以硫化氢供体药物NaHS(1mg·kg^-1,i.p.)或生理盐水。高脂饮食24周后,通过超声生物显微镜成像技术评估小鼠主动脉及其主要分支内的动脉粥样硬化情况,随后处死小鼠并留取主动脉,通过H&E染色和免疫组化技术进一步观察小鼠头臂干动脉粥样斑块的病变情况及CX3CR1的表达水平。结果在动脉粥样硬化斑块形成早期,即出现了CSE表达水平的显著降低,随着斑块的进展,CSE的表达水平进一步下调和CSE活性明显下降,最终导致血浆硫化氢水平的显著降低。动脉粥样硬化早期或中晚期予以NaHS均可显著延缓动脉粥样硬化斑块的形成和进展,但是NaHS早期干预,其抗动脉粥样化的益处显著优于中晚期干预。NaHS的抗动脉粥样硬化益处可能与其抑制斑块内CX3CR1的表达有关。结论动脉粥样硬化过程中存在着内源性硫化氢代谢紊乱,予以NaHS干预可抑制斑块内CX3CR1的表达和延缓动脉粥样硬化的进展,早期NaHS干预的疗效显著优于中晚期干预。Objective To investigate the potential role of H2S in the pathogenesis of atherosclerosis and the underlying mechanism with respect to chemokine receptor CX3CR1 expression in atherosclerotic plaques. Methods Ten-week old, male Apo E-/- mice were fed a high-fat diet and then were sacrificed 4, 8, 12, or 24 weeks after fat feeding. Plasma levels of H2S, H2S synthesizing activity and cystathionine-γ- lyase （CSE） expression in aorta were measured by chemical colorimetry and western blot respectively. Some Apo E-γ- mice were given NariS （lmg.kg^-1, i.p., daily）, an H2S donor either 4 weeks or 12 weeks after fat feeding. Twenty-four weeks after fat feeding, mice were sacrificed and analyzed for the extent of atherosclerosis by ultrasound biomicroscopy and CX3CR1 expression in plaques by histological analysis. Results We found that the plasma H2S concentration and endogenous H2S formation in aorta were decreased in a time-dependent manner during the development of atherosclerosis. Either early or delayed-NariS treatment significantly downregulated CX3CR1 expression in atherosclerotic plaques and impeded plaque development in aorta. Interestingly, NariS seemed to have a better anti-atherogenic benefit when it was applied during the early stage of atherosclerosis. Conclusion These data indicate that deficiency of endogenous H2S formation in aorta accompanies the development and progression of atherosclerosis. H2S may prevent the progression of atheroselerosis by downregulating CX3CR1 expression in plaques.

关 键 词：硫化氢 胱硫醚-Γ-裂解酶 动脉粥样硬化 CX3CR1 

分 类 号：R543.5[医药卫生—心血管疾病]