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中国人民解放军总医院老年心血管病研究所
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中华老年多器官疾病杂志编辑委员会
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创刊人 王士雯
总编辑 范利
副总编辑 陈韵岱
执行主编 叶大训
编辑部主任 王雪萍
ISSN 1671-5403
CN 11-4786
创刊时间 2002年
出版周期 月刊
邮发代号 82-408
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杜高波,唐其柱.罗氟司特对压力超负荷诱导的小鼠心肌重构的影响及其机制[J].中华老年多器官疾病杂志,2020,19(12):930~936
罗氟司特对压力超负荷诱导的小鼠心肌重构的影响及其机制
Effects of roflumilast on cardiac remodeling induced by pressure overload in mice and its mechanism
投稿时间:2020-01-02  
DOI:10.11915/j.issn.1671-5403.2020.12.213
中文关键词:  罗氟司特;心肌肥厚;心肌纤维化;炎症;p38丝裂原激活的蛋白激酶
英文关键词:roflumilast; cardiac hypertrophy; cardiac fibrosis; inflammation; p38MAPK This work was supported by the National Natural Science Foundation of China
基金项目:国家自然科学基金(81530012;81470516)
作者单位
杜高波 武汉大学人民医院心内科,武汉大学心血管病研究所,心血管病湖北省重点实验室,武汉430060 
唐其柱 武汉大学人民医院心内科,武汉大学心血管病研究所,心血管病湖北省重点实验室,武汉430060 
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中文摘要:
      探讨罗氟司特(RM)对压力负荷诱导的小鼠心肌重构的作用及机制。方法 利用主动脉缩窄术(AB)构建小鼠心肌重构模型,采用随机数表法,将40只雄性C57/B6小鼠(8~10周)随机分为假手术组(Sham组),AB组,AB+RM(1mg/kg)组及AB+RM(3mg/kg)组,每组10只。AB术后第2天给予小鼠RM灌胃处理,连续灌胃至术后6周。随后行超声心动图检测各组小鼠心脏功能,包括左室射血分数(LVEF)、左室短轴缩短率(LVFS)、左室收缩末期内径(LVESD)及左室舒张末期内径(LVEDD);采用HE及天狼猩红染色观察各组心脏组织肥厚及纤维化状况;采用qPCR 法检测心肌肥厚,纤维化及炎症相关基因的mRNA 的表达,包括心钠素、脑利钠肽、β-MHC、结缔组织生长因子、fibronectin、collagen1、collagan3、白细胞介素-6(IL-6)及肿瘤坏死因子-α(TNF-α);采用免疫组织化学染色标记CD45及CD68检测心肌组织白细胞和巨噬细胞浸润水平;采用蛋白免疫印迹法检测心肌组织中磷酸化的p38(P-p38)及总p38(T-p38)的蛋白表达水平。采用 SPSS 22.0 统计学软件进行数据分析。结果 术后6周,与Sham组相比,AB组小鼠LVEF及LVFS水平显著降低,LVESD及LVEDD水平明显升高,心肌肥厚及心肌纤维化水平明显升高,心肌组织中CD45、CD68、IL-6及TNF-α的蛋白表达水平明显增高(P<0.05);与AB组相比,AB+RM(1mg/kg)组及AB+RM(3mg/kg)组小鼠心功能明显改善,心肌肥厚及纤维化水平明显被抑制,心肌组织炎症水平明显降低(P<0.05);免疫印迹结果显示,RM(1及3mg/kg)能够明显抑制AB诱导的小鼠心肌组织p38的磷酸化(P<0.05)。结论 罗氟司特可减轻压力负荷诱导的小鼠心肌肥厚及纤维化,主要通过调节p38丝裂原激活的蛋白激酶信号通路及炎症反应发挥上述作用。
英文摘要:
      Objective To investigate the effects of roflumilast (RM) on cardiac remodeling induced by pressure overload in mice and its mechanism. Methods Aortic constriction (AB) was used to construct a mice model of cardiac remodeling. A total of 40 male C57/B6 mice (8-10 weeks) were randomly divided into sham group, AB group, AB + RM (1mg / kg) group, and AB + RM (3mg/kg) group (n=10each). At d 2 after AB surgery, the mice were given an intragastric administration of RM for 6 weeks. Echocardiography was performed to detect cardiac function in each group, including left ventricular ejection fraction (LVEF), left ventricular short axis fraction shortening (LVFS), left ventricular end systolic diameter (LVESD), and left ventricular end diastolic diameter (LVEDD). HE and Picrosirius Red staining were used to observe cardiac hypertrophy and fibrosis, and qPCR was used to detect the mRNA expression levels of cardiac hypertrophy, fibrosis and inflammation-related genes, including atriopeptin, brain natriuretic peptide, β-MHC, connective tissue growth factor, fibronectin, collagen 1,collagan 3, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Immunohistochemical markers CD45 and CD68 were used to detect leukocyte and macrophage infiltration in cardiac tissue. Western blot was used to detect the protein expression level of phosphorylated p38 (P-p38) and total p38 (T-p38). Results At week 6 after AB surgery, compared with the Sham group, LVEF and LVFS in the AB group were significantly reduced, the LVESD and LVEDD were significantly increased, the cardiac hypertrophy and fibrosis were significantly increased, and CD45 and CD68 in cardiac tissue, the expression levels of IL-6 and TNF-α were significantly increased (P<0.05). Compared with the AB group, the cardiac function of the AB+RM (1mg/kg) group and the AB+RM (3mg/kg) group was significantly improved, cardiac hypertrophy and fibrosis were significantly suppressed, and inflammation was significantly reduced (P<0.05). Western blot results showed that RM (1 and 3mg/kg) could significantly inhibit the p38 of cardiac tissue induced by AB surgery (P<0.05). Conclusion Roflumilast can reduce overload-induced cardiac hypertrophy and fibrosis in mice mainly through regulating the p38 MAPK signaling pathway and inflammatory response.
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