2-羟基苄胺改善衰老相关动脉粥样硬化的机制研究  

2-hydroxybenzylamine(2-HOBA)curbs the pathogenesis of aging-associated atherosclerosis

作　　者：王恩昊 罗鹏程 刘彧[1] 张存泰[1] Wang Enhao;Luo Pengcheng;Liu Yu;Zhang Cuntai(Institute of Aging,Department of Geriatrics,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China)

机构地区：[1]华中科技大学同济医学院附属同济医院综合医疗科,华中科技大学同济医学院附属同济医院老年病研究所,湖北省老年医学中心,武汉430030

出　　处：《中华老年医学杂志》2023年第6期720-725,共6页Chinese Journal of Geriatrics

基　　金：国家重点研发计划(2020YFC2008000);国家自然科学基金(81801386);武汉市科技局专项基金(2022020801020452)。

摘　　要：目的探索不同浓度2-羟基苄胺(2-HOBA)对动脉粥样硬化和血管平滑肌细胞衰老的影响及相关作用机制。方法使用载脂蛋白E基因缺陷(ApoE^(-/-))小鼠14只建立动脉粥样硬化模型,ApoE-/-小鼠数字抽签法分为2组(每组7只):高脂饮食(HD)组和高脂饮食加2-HOBA(1mg/ml)饮水喂药(HD+HOBA)组。脉搏波传导速度检测血管硬度,同时使用跑步机检测运动耐力,油红O染色法检测动脉粥样斑块的大小及数量,Masson染色检测斑块内部胶原纤维、弹力纤维的形态,斑块核心坏死区域的大小及纤维帽的厚度。小鼠平滑肌细胞分别使用不同浓度的2-HOBA(100μmol/L、250μmol/L和500μmol/L)干预过氧化氢诱导的应激衰老模型,衰老相关β-半乳糖苷酶染色检测细胞衰老程度,应用实时荧光定量聚合酶链式反应(RT-qPCR)检测衰老相关分泌表型因子的mRNA表达水平,同时使用免疫印迹法检测衰老相关信号蛋白表达水平。结果与高HD组小鼠比较,HD+HOBA组小鼠在2-HOBA的干预下主动脉粥样斑块面积与数量减小,同时稳定粥样斑块。此外,与HD组小鼠主动脉血管硬度(3.50±0.28)mm/ms比较,HD+2-HOBA组小鼠(2.59±0.32)mm/ms下降26%,差异有统计学意义(P<0.01),运动耐力(143.74±24.25)m比(233.50±30.21)m提高约62%(P<0.01),提示2-HOBA能改善小鼠主动脉血管硬度和运动耐力。2-HOBA可改善由过氧化氢诱导的血管平滑肌细胞衰老,同时降低过氧化氢诱导的衰老相关分泌表型相关因子如白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α及单核细胞趋化蛋白-1的mRNA水平。同时,2-HOBA还可抑制衰老关键信号因子p53及p21的表达。结论2-HOBA通过抑制氧化应激相关p53/p21信号激活,改善血管平滑肌细胞衰老及衰老相关炎症分泌表型,改善动脉粥样硬化的形成及发展。Objective To explore the effects of different concentrations of 2-hydroxybenzylamine(2-HOBA)on atherosclerosis and vascular smooth muscle cell senescence and the underlying mechanisms.Methods Fourteen apolipoprotein E-deficient(ApoE-/-)mice were used to establish an atherosclerosis model and were divided into two groups(n=7)using the random number method:a high-fat diet(HD)group and a high-fat diet plus 2-HOBA(1 mg/ml)(HD+HOBA)group.Pulse wave velocity was used to assess vascular stiffness and a treadmill was used to assess exercise endurance.Oil Red O staining was used to detect the size and number of atherosclerotic plaques.Masson staining was used to detect the morphology of collagen fibers and elastic fibers in the plaque,the size of the necrotic core area of the plaque,and the thickness of the fibrous cap.Mouse smooth muscle cells were treated with different concentrations of 2-HOBA(100μmol/L,250μmol/L and 500μmol/L)to establish an H_(2)O_(2)-induced senescence mnodel.Senescence-associated β-galactosidase staining was used to detect cell senescence.Real-time quantitative polymerase chain reaction(RT-qPCR)was used to detect the mRNA expression levels of senescence-related secretory phenotype factors,and Western blot was used to detect the expression levels of senescence-related signaling proteins.Results Compared with the HD group,the HD+HOBA group showed that the area and number of aortic atherosclerotic plaques were decreased,and the atherosclerotic plaques were stabilized.In addition,compared with the HD group,vascular stiffness in the HD+2-HOBA group decreased by 26%(2.59±0.32 mm/ms vs.3.50±0.28 mm/ms),with a statistically significant difference(P<0.01),and exercise endurance increased by 62%[(143.74±24.25)m vs.(233.50±30.21)m,P<0.01],suggesting that 2-HOBA was able to improve aortic vascular stiffness and exercise endurance in mice.2-HOBA ameliorated H_(2)O_(2)-induced vascular smooth muscle cell senescence and decreased the mRNA levels of H_(2)O_(2)-induced senescence-associated secretory phenot

关 键 词：动脉粥样硬化 肌 平滑 血管 2-羟基苄胺 

分 类 号：R543.5[医药卫生—心血管疾病]