牡荆素调节环磷酸腺苷激活的交换蛋白1/钙/钙调素依赖性蛋白激酶Ⅱ信号对大鼠心肌梗死后心肌肥大与纤维化的作用  

Effects of vitexin on cardiac hypertrophy and fibrosis after myocardial infarction in rats through modulation of the exchange proteins activated directly by cyclic adenosinemonophosphate 1/calcium/calmodulin-dependent protein kinaseⅡpathway

作　　者：赵天昊 袁慧 麻祖青 陶星宇 张宇 董六一 Zhao Tianhao;Yuan Hui;Ma Zuqing;Tao Xingyu;Zhang Yu;Dong Liuyi(Department of Pharmacology,School of Basic Medicine,Anhui Medical University,Hefei 230032,China)

机构地区：[1]安徽医科大学基础医学院药理学教研室,合肥230032

出　　处：《心脑血管病防治》2024年第2期10-15,共6页CARDIO-CEREBROVASCULAR DISEASE PREVENTION AND TREATMENT

基　　金：安徽省自然科学基金(2108085MH254)。

摘　　要：目的探讨牡荆素调控环磷酸腺苷激活的交换蛋白1(Epac1)/钙/钙调素依赖性蛋白激酶Ⅱ(CaMKⅡ)信号通路抑制大鼠心肌梗死(MI)后心肌细胞肥大与纤维化的作用。方法24只SD大鼠随机分为:假手术组、MI组、牡荆素组。大鼠进行心脏左前降支结扎建立MI模型,假手术组只穿线不结扎。检测大鼠心功能变化;苏木精-伊红(HE)染色观察心脏病理学变化,天狼星红染色观察心脏纤维化,电镜观察心肌线粒体损伤情况;Western Blot检测Epac1、CaMKⅡ等蛋白变化。结果(1)大鼠MI 4周后,与假手术组比较MI组大鼠左心室短轴缩短率(LVFS)和左心室射血分数(LVEF)均降低(P<0.01),左心室收缩末期内径(LVIDs)、左心室舒张末期内径(LVIDd)和舒张末期左心室后壁厚度(LVPWd)、收缩末期左心室后壁厚度(LVPWs)增加(P<0.01),牡荆素组大鼠心脏LVIDs、LVIDd、LVPWs和LVPWd较MI组降低,LVFS和LVEF均升高,差异有统计学意义(P<0.05);(2)牡荆素可降低大鼠心脏重量指数(P<0.01),并减小MI组大鼠心肌细胞横截面积,同时减轻大鼠左心室壁心肌纤维化程度(P<0.01),牡荆素组大鼠心肌胞浆内线粒体肿胀较MI组减轻,线粒体形态较完整,空泡形成较少;(3)Western Blot结果显示牡荆素抑制大鼠MI后Epac1激活(P<0.01),抑制其下游CaMKⅡ激活与细胞外调节激酶的磷酸化(P<0.01),同时可抑制B淋巴细胞瘤-2(Bcl-2)相关X蛋白(Bax)上调(P<0.05),上调Bcl-2(P<0.01),抑制凋亡蛋白裂解半胱天冬酶3(Cleaved-Caspase 3)的活化(P<0.05)。结论牡荆素可通过抑制Epac1/CaMKⅡ通路,改善大鼠MI后心脏功能,抑制心肌肥大和纤维化。Objective To explore the role of vitexin in regulating the exchange proteins activated directly by cyclic adenosinemonophosphate1(Epac1)/calcium/calmodulin-dependent protein kinaseⅡ(CaMKⅡ)signaling pathway and inhibiting myocardial cell hypertrophy and fibrosis in rats after myocardial infarction(MI).Methods Twenty-four SD rats were randomly divided into sham surgery group,MI group,and vitexin group.The MI model was established by left anterior descending coronary artery ligation.In the sham surgery group,the left anterior descending coronary artery was only threaded without ligation.Changes in rat cardiac function were assessed.Cardiac pathological changes were observed using hematoxylin-eosin(HE)staining,and fibrosis was assessed using Sirius Red staining.Mitochondrial damages in cardiocytes were examined by electron microscopy.Western blot was used to detect protein changes,including Epac1 and CaMKⅡ.Results(1)Four weeks after MI,compared with the sham surgery group,left ventricular fractional shortening(LVFS)and left ventricular ejection fraction(LVEF)in the MI group decreased(P<0.01),and left ventricular internal diameter at end-systolic(LVIDs),left ventricular internal diameter at end-diastolic(LVIDd),left ventricular posterior wall thickness at end-diastolic(LVPWd),and left ventricular posterior wall thickness at end-systolic(LVPWs)inceased(P<0.01).The vitexin group showed significant decreases in LVIDs,LVIDd,LVPWs,and LVPWd and increases in LVFS and LVEF compared to the MI group(P<0.05).(2)Vitexin reduced the heart weight index(P<0.01)and decreased the cross-sectional area of myocardial cells in rats of MI group,while alleviating myocardial fibrosis in the left ventricular wall(P<0.01).In the vitexin group,myocardial cytoplasmic mitochondrial swelling was reduced,mitochondrial morphology was more intact,and vacuole formation was decreased compared to the MI group.(3)Western blot results showed that vitexin inhibited Epac1 activation(P<0.01),suppressed the activation of downstream CaMKⅡand the phosp

关 键 词：牡荆素 心肌缺血 凋亡 环磷酸腺苷激活的交换蛋白1 钙/钙调素依赖性蛋白激酶Ⅱ 

分 类 号：R285.5[医药卫生—中药学]