葫芦巴碱通过激活磷脂酰肌醇3激酶/蛋白激酶B信号通路改善失代偿性心力衰竭小鼠心肌纤维化和心功能  

Trigonelline ameliorates myocardial fibrosis and cardiac function via activating phosphatidylinositol3 kinase(PI3K)/protein kinase B(Akt)signaling pathway in mice with decompensated heart failure

作　　者：辛婷婷[1] 李红超 臧富成 臧慧梅 苏磊 XIN Tingting;LI Hongchao;ZANG Fucheng;ZANG Huimei;SU Lei(Department of Critical Care Medicine,Linyi People's Hospital,Linyi 276003,Shandong,China;Department of Breast and Thyroid Surgery,Linyi People's Hospital,Linyi 276003,Shandong,China;Department of Rehabilitation Medicine,Affiliated Hospital of Xuzhou Medical University;Medical Colledge of Qingdao Binhai University;Department of Neurology,Shandong Veterans General Hospital)

机构地区：[1]临沂市人民医院重症医学科,山东临沂276003 [2]临沂市人民医院乳腺甲状腺外科,山东临沂276003 [3]徐州医科大学附属医院康复医学科 [4]青岛滨海学院医学院 [5]山东省荣军总医院神经内科

出　　处：《中华高血压杂志（中英文）》2024年第5期470-481,共12页Chinese Journal of Hypertension

基　　金：山东省医药卫生科技发展计划项目(202102080593);青岛市中医药科技项目(2022-zyyq12)。

摘　　要：目的研究葫芦巴碱(Trig)对小鼠失代偿性心力衰竭的影响并探讨其可能作用机制。方法采用主动脉弓缩窄(TAC)术构建心脏后负荷压力增高型心力衰竭小鼠模型。将96只C57BL/6J小鼠分成假手术(Sham)组(n=8),Sham+Trig低、中、高剂量[20、40、80 mg/(kg·d)]组(n=8),TAC组(n=16),TAC+Trig低、中、高剂量[20、40、80 mg/(kg·d)]组(n=16)。Trig灌胃治疗8周后取材。记录各组小鼠生理指标(体重、心脏重量、心肺指数等)。采用超声心动图检测心功能,采用病理学检验分析心肌纤维化水平及心肌细胞凋亡率。提取RNA检测心力衰竭因子[心房利尿钠肽(ANP)、脑利尿钠肽(BNP)、α-肌球蛋白重链(α-MHC)、β-肌球蛋白重链(β-MHC)]的表达,提取蛋白检测心脏Smad3、转化生长因子β_(1)(TGF-β_(1))、B细胞淋巴瘤2(Bcl-2)、Bcl-2关联X蛋白(Bax)及磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(Akt)通路蛋白的表达水平。结果与Sham组相比,TAC组小鼠左心室内径(LVID)、左心室后壁厚度(LVPWT)、室间隔厚度(IVST)增加,射血分数(EF)、短轴缩短率(FS)[(26.25±2.88)%比(41.0±2.54)%,t=11.12,P<0.001]及心输出量降低;心肌间质及管周胶原纤维堆积,心肌细胞凋亡率增加;心力衰竭因子及TGF-β_(1)、p-Smad3、Ⅰ型胶原蛋白及Ⅲ型胶原蛋白表达增加,PI3K、Akt表达下降(均P<0.05);与TAC组相比,TAC+Trig低、中剂量组LVID、LVPWT和IVST降低,EF、FS及心输出量增加,心力衰竭因子及TGF-β_(1)、p-Smad3、Ⅰ型胶原蛋白及Ⅲ型胶原蛋白表达下降,Bcl-2/Bax及PI3K、Akt蛋白表达上调,且以中剂量组改善更显著(均P<0.05);心肌间质及管周胶原纤维堆积被抑制,心肌细胞凋亡率下降(均P<0.05)。结论Trig能够改善心力衰竭小鼠心脏功能,减轻心肌间质及管周胶原纤维堆积,抑制心肌细胞凋亡,其作用机制可能与激活PI3K/Akt通路有关。Objective To investigate the protective role of Trigonelline(Trig)on decompensated heart failure in mice and explore its possible mechanisms.Methods Transverse aortic arch constriction(TAC)surgery was used to construct a heart failure model in mice with increased cardiac afterload pressure.A total of 96 C57BL/6J mice were randomly divided into the Sham group(n=8),Sham+Trig low-dose,medium-dose and high-dose[20,40,80 mg/(kg·d)]group(n=8),TAC group(n=16),TAC+Trig low-dose,medium-dose and high-dose[20,40,80 mg/(kg·d)]group(n=16).Samples were harvested after 8 weeks of gavage treatment.Physiological indexes(body weight,heart weight,cardiopulmonary index)of mice in each group were recorded.Echocardiography was used to detect cardiac function,and pathology was performed to analyze the level of myocardial fibrosis and the rate of cardiomyocyte apoptosis.RNA was extracted to detect the expression of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),alpha-myosin heavy chain(α-MHC),beta-myosin heavy chain(β-MHC),and proteins were extracted to detect cardiac Smad3,transforming growth factor-beta1(TGF-β_(1)),B cell lymphoma 2(Bcl-2),pro-apoptotic Bcl-2-associated X(Bax),and phosphatidylinositol3 kinase(PI3K)/protein kinase B(Akt)pathway.Results Compared with the Sham group,the values of left ventricular internal diameter(LVID),left ventricular posterior wall thickness(LVPWT),interventricular septal thickness(IVST)in TAC group mice were significantly increased,ejection fraction(EF),fraction shortening(FS)[(26.25±2.88)%vs(41.0±2.54)%,t=11.12,P<0.001]and cardiac output(CO)were significantly decreased;myocardial interstitial and perivascular fibrosis were accumulated,and myocyte apoptosis rate was elevated;protein expressions of heart failure factors,as well as TGF-β_(1),p-Smad3,CollagenⅠandⅢwere enhanced,and expression of PI3K/Akt pathway proteins were decreased(all P<0.05);compared with the TAC group,LVID,LVPWT,and IVST were decreased in TAC+Trig low-dose and medium-dose groups;EF,FS,and CO were increa

关 键 词：胡芦巴碱 主动脉缩窄手术 心肌纤维化 心力衰竭 磷脂酰肌醇3-激酶 蛋白激酶B 

分 类 号：R285.5[医药卫生—中药学]