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小檗碱通过Notch信号通路改善心肌梗死大鼠心肌纤维化的作用机制

Action mechanism of berberine for myocardial fibrosis improvement of rats with myocardial infarction via Notch signaling pathway
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摘要 目的探讨小檗碱对心肌梗死(MI)大鼠心肌纤维化改善的作用机制。方法将60只大鼠用随机数字表法取10只作为假手术组,其余50只采用冠状动脉结扎法制备MI模型。将造模成功的40只大鼠用随机数字表法分为模型组、美托洛尔组、小檗碱低剂量组和小檗碱高剂量组,每组10只。造模48 h后,小檗碱低剂量组、高剂量组分别给予小檗碱50、100 mg/kg灌胃,美托洛尔组给予美托洛尔10 mg/kg灌胃,假手术组、模型组给予生理盐水2 mL/d灌胃,1次/d,共干预30 d。记录各组体质量,HE染色后观察心肌组织病理变化,用天狼星红染色法检测心肌组织中胶原纤维含量,用免疫组化染色法检测心肌组织中基质金属蛋白酶1(MMP-1)、MMP-9蛋白,用Western blotting法检测心肌组织中Notch通路关键蛋白(Hey1、Hes1)、神经生长因子(NGF)、α-平滑肌肌动蛋白(α-SMA)蛋白。结果与假手术组比较,模型组各时间点体质量低(P<0.05)。与模型组比较,给药组各时间点体质量高(P<0.05)。假手术组大鼠心肌组织未见异常变化。模型组大鼠心肌组织紊乱,心肌细胞变性、坏死明显,细胞间质水肿明显,有大量炎性细胞浸润。各治疗组心肌细胞变性坏死得到改善,且小檗碱高剂量组改善最显著。与假手术组比较,模型组心肌组织中胶原纤维含量高(P<0.05);与模型组比较,美托洛尔组、小檗碱低剂量组、小檗碱高剂量组心肌组织中胶原纤维含量均低(P<0.05)。与假手术组比较,模型组大鼠心肌组织中MMP-1、MMP-9蛋白表达量高(P<0.05);与模型组比较,美托洛尔组、小檗碱低剂量组、小檗碱高剂量组MMP-1、MMP-9蛋白表达均低(P<0.01)。与假手术组比较,模型组大鼠心肌组织中Hes1、Hey1、NGF、α-SMA蛋白表达高(P<0.05);与模型组比较,美托洛尔组、小檗碱高剂量组、小檗碱低剂量组Hes1、Hey1、NGF、α-SMA蛋白表达均低(P<0.01)。结论小檗碱可通过Notch信号通路抑制心肌梗死(MI)大鼠心肌纤维化。 Objective To investigate the effect of berberine on improving myocardial fibrosis in rats with myocardial infarction(MI).Methods Among the 60 rats,according to the random number table method,ten were chosen as the sham operation group,with the remaining 50 adopted to build an MI model by utilizing the coronary artery ligation method.Then,the 40 successfully modeled rats were divided into the model group,metoprolol group,low-dose berberine group,and high-dose berberine group,with ten rats in each group.After modeling for 48 hours,gavage administration was conducted with berberine on the high-dose(50 mg/kg)and low-dose(100 mg/kg)berberine groups,metoprolol(10 mg/kg)on the metoprolol group,and physiological saline(2 mL/d)on the sham operation group and model group.The treatment was carried out once a day for 30 days.Additionally,the body mass of each group was recorded,and the pathological changes of cardiac muscular tissue after HE staining were observed,with the collagen fiber content in cardiac muscular tissue detected by Sirius red staining.The matrix metalloproteinase-1(MMP-1)and MMP-9 proteins in cardiac muscular tissue were detected by immunohistochemistry staining,and the key proteins of the Notch pathway(Hey1 and Hes1),nerve growth factor(NGF),andαsmooth muscle actin(α-SMA)proteins in cardiac muscular tissue were also detected by Western blotting.Results The model group had lower body mass at all time points than the sham operation group(P<0.05),and compared with the model group,the administration groups’body mass at all time points was higher(P<0.05).Meanwhile,there was no abnormal change in the cardiac muscular tissue of rats in the sham operation group.The cardiac muscular tissue of rats in the model group was disordered,and cardiac muscle cells had obvious degeneration and necrosis,with notable edema in intercellular substances and abundant inflammatory cell infiltration.The degeneration and necrosis of each treatment group were improved in treatment groups,with the most remarkable improvement in the high-dose berberine group.Compared with the sham operation group,the collagen fiber content in the cardiac muscular tissue of the model group was higher(P<0.05),while that of the metoprolol group,low-dose berberine group,and high-dose berberine group was lower than the collagen fiber content of the model group(P<0.05).Compared with the sham operation group,the expression of MMP-1 and MMP-9 proteins in the cardiac muscular tissue of rats in the model group was higher(P<0.05),while that of MMP-1 and MMP-9 proteins in the metoprolol group,high-dose berberine group and low-dose berberine group was lower than that of the model group(P<0.01).Compared with the sham operation group,the expression of Hes1,Hey1,NGF,and a-SMA proteins in the cardiac muscular tissue of rats in the model group was higher(P<0.05).Compared with the model group,the expression of Hes1,Hey1,NGF,andα-SMA proteins in the metoprolol group,high-dose berberine group,and low-dose berberine group was lower(P<0.01).Conclusion Berberine can inhibit myocardial fibrosis of MI rats via the Notch signaling pathway.
作者 马鑫 戴方圆 张启明 李平 MA Xin;DAI Fangyuan;ZHANG Qiming;LI Ping(School of Life Sciences,Beijing University of Chinese Medicine,Beijing 102401,China;Department of Cardiology,Beijing University of Chinese Medicine Third Affiliated Hospital,Beijing 100029)
出处 《北京中医药》 2024年第11期1281-1286,共6页 Beijing Journal of Traditional Chinese Medicine
基金 国家自然科学基金资助项目(81960852)。
关键词 心肌梗死 小檗碱 纤维化 NOTCH信号通路 大鼠 Myocardial infarction berberine fibrosis Notch signaling pathway rat
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