柚皮素通过调控平滑肌细胞TIMP-3表达促进动脉粥样硬化斑块稳定  

Naringenin promotes atherosclerotic palque stability by regulating the expression of TIMP-3 in smooth muscle cells

作　　者：何慧 董豆豆 丁萌 朱沅 姜天宇 许晓婷 欧海龙 HE Hui;DONG Doudou;DING Meng;ZHU Yuan;JIANG Tianyu;XU Xiaoting;OU Hailong(Department of Biochemistry and Molecular Biology,School of Basic Medicine,Guizhou Medical University,Guiyang,Guizhou 561113,China)

机构地区：[1]贵州医科大学基础医学院生物化学与分子生物学教研室,贵州省贵阳市561113

出　　处：《中国动脉硬化杂志》2024年第7期567-572,582,共7页Chinese Journal of Arteriosclerosis

基　　金：国家自然科学基金项目(32260232、32060219);贵州省科技基金项目(黔科合基础-ZK[2022]重点038)。

摘　　要：[目的]探究柚皮素对动脉粥样硬化斑块胞外基质重构和斑块稳定性的影响。[方法]分离原代小鼠血管平滑肌细胞,进行不同剂量的柚皮素处理。对高脂诱导的ApoE-/-小鼠进行柚皮素灌胃16周,天狼星红-苏木精染色分析主动脉根部斑块坏死核面积、斑块内胶原含量和纤维帽厚度,Van Gieson染色检测弹力蛋白降解,明胶酶谱法和荧光标记明胶法检测斑块内基质金属蛋白酶(MMP)活性。[结果]柚皮素(50μmol/L)促进平滑肌细胞信号转导及转录活化因子6(STAT6)磷酸化和组织型基质金属蛋白酶抑制剂3(TIMP-3)的转录活性,TIMP-3的表达升高3.1倍(P<0.001)。柚皮素(80 mg/kg)处理后,与对照组相比,主动脉根部斑块坏死核面积降低53%(P<0.01)、纤维帽厚度提高近50%(P<0.05),弹力纤维降解程度降低。同时,柚皮素促进斑块内TIMP-3的表达,斑块内MMP活性也相应降低。慢病毒介导的体内抑制TIMP-3表达可降低柚皮素对斑块稳定的保护作用。[结论]柚皮素通过提高平滑肌细胞内TIMP-3表达,改善细胞外基质成分,促进动脉粥样硬化斑块稳定。Aim To investigate the effects of naringenin on atherosclerotic plaque extracellular matrix remodeling and plaque stability.Methods Murine vascular smooth muscle cells were isolated and treated with various doges of naringenin.ApoE-/-mice were fed with high-fat diet and received naringenin by lavage for 16 weeks.Intraplaque nec-rotic core,contents of collagen and fibrous cap thickness were measured by Sirius red-Haematoxylin staining.Elastin was detected by Van Gieson staining.Matrix metalloproteinase(MMP)activity was determined by gelatin zymography and fluorescence-gelatin staining.Results Naringenin(50μmol/L)increased signal tansducer and activator of transciption 6(STAT6)phosphorylation and promoted tissue inhibitor of metalloproteinase-3(TIMP-3)expression by 3.1-fold(P<0.001).After naringenin(80 mg/kg)treatment,compared with the control group,the area of plaque necrotic core in aor-tic root decreased by 53%(P<0.01),the thickness of fibrous caps increased by nearly 50%(P<0.05),and the degree of elastic fiber degradation decreased.At the same time,naringenin promoted the expression of TIMP-3 in plaques,and corre-spondingly reduced the activity of MMP in plaques.Lentivirus mediated inhibition of TIMP-3 expression in vivo could reduce the protective effect of naringenin on plaque stability.Conclusion Naringin can increase the expression of TIMP-3 in smooth muscle cells,improve the composition of extracellular matrix,and promote the stability of atherosclerotic plaque.

关 键 词：柚皮素 信号转导及转录活化因子6 组织型基质金属蛋白酶抑制剂3 动脉粥样硬化 斑块稳定性 

分 类 号：R5[医药卫生—内科学] R363[医药卫生—临床医学]