摘要
目的 观察沉默信息调节因子1(sirtuin 1,SIRT1)对压力超负荷致大鼠心肌纤维化及血管紧张素Ⅱ(angiotensin, AngⅡ)诱导的大鼠心脏成纤维细胞增殖的影响,并探讨其分子机制。方法 在体实验通过不完全结扎大鼠腹主动脉,使压力负荷增加诱导心肌纤维化,给予SIRT1激活剂后,左室心肌组织行Masson染色,观察心肌间质纤维化并计算胶原容积分数,免疫组化染色检测心肌组织TGF-β1/Smads蛋白表达。提取新生大鼠心脏成纤维细胞,给予AngⅡ或AngⅡ加SIRT1激活剂后,采用MTT法检测细胞增殖,qRT-PCR和Western blot法检测心肌组织及成纤维细胞Ⅰ型、Ⅲ型胶原(collagenⅠ/Ⅲ,Col1α1/3α1)、SIRT1及TGF-β1/Smads mRNA及蛋白的表达。结果 与假手术组相比,压力超负荷模型组大鼠心肌间质出现显著的纤维化,心肌胶原容积分数增加,Col1α1/3α1、TGF-β1/Smads表达明显增多,SIRT1表达减少;给予SIRT1激活剂SRT1720干预后可改善压力超负荷诱导的心肌间质纤维化,下调Col1α1/3α1、TGF-β1/Smads表达,上调SIRT1的表达;同时,相关性分析显示SIRT1的蛋白表达与TGF-β1的表达呈负相关。另外,SRT1720亦可抑制AngⅡ诱导的成纤维细胞增殖、Col1α1/3α1及TGF-β1表达的增加。结论 激活SIRT1对压力超负荷导致的心肌纤维化及AngⅡ诱导的成纤维细胞增殖均有显著的抑制作用,其可能通过调节TGF-β1/Smads信号通路抑制或逆转心肌纤维化的发生。
Objective To observe the effect of sirtuin 1(SIRT1)on rat myocardial fibrosis induced by pressure overload and the proliferation of cardiac fibroblasts induced by angiotensinⅡ(AngⅡ),and to explore the molecular mechanisms.Methods The pressure overload-induced myocardial fibrosis was established by abdominal aorta constriction(AAC)procedure in vivo.After treatment with SIRT1activator,the myocardial interstitial fibrosis and the collagen volume fraction were evaluated by Masson’s trichrome staining.The protein expressions of TGF-β1/Smads were determined by immunohistochemical analysis.After in vitro intervention of AngⅡor AngⅡwith SIRT1activator,the fibroblasts proliferation was detected by MTT assay.The mRNA and protein expressions of collagenⅠ/Ⅲ(Col1α1/3α1),SIRT1and TGF-β1/Smads in myocardial tissue and fibroblasts were evaluated by qRT-PCR and Western blotting.Results Compared with the sham operation group,myocardial interstitial fibrosis was significantly observed in the pressure overload model group,myocardial collagen volume fraction was increased,expressions of Col1α1/3α1and TGF-β1/Smads were significantly increased,and SIRT1expression was decreased.After the intervention of SRT1720,SIRT1activator could improve the myocardial interstitial fibrosis induced by pressure overload,downregulate the expressions of Col1α1/3α1and TGF-β1/Smads,and upregulate the expression of SIRT1.Meanwhile,correlation analysis showed that the protein expression of SIRT1was negatively correlated with the expression of TGF-β1.In addition,SRT1720also inhibited AngⅡ-induced fibroblast proliferation and increased expression of Col1α1/3α1and TGF-β1.Conclusion Activation of SIRT1inhibits pressure overload-induced myocardial fibrosis and AngⅡ-induced fibroblasts proliferation via regulation of the TGF-β1/Smads signaling pathway.
作者
何婷
陈军
庞牧
杨昊
张俊志
He Ting;Chen Jun;Pang Mu(Department of Pharmacy,Shenzhen Traditional Chinese Medicine Hospital,the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine,Shenzhen 518033,China)
出处
《华中科技大学学报（医学版）》
CAS
CSCD
北大核心
2024年第1期45-51,共7页
Acta Medicinae Universitatis Scientiae et Technologiae Huazhong
基金
国家自然科学基金青年基金项目(No.81700435)
广东省医学科研基金项目(No.A2022060)。
