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目的:探讨黄芩苷对阿霉素(ADR)诱导扩张型心肌病大鼠心室重构、心室肌细胞凋亡及β-AR/PKA/CaMK Ⅱ信号通路的影响。方法:雄性Wistar大鼠60只,随机分为正常组、模型组、黄芩苷低、中、高剂量组及卡维地洛组;模型组给予ADR 2 mg·kg~(-1)腹腔注射,黄芩苷组及卡维地洛组在模型组基础上分别给予黄芩苷(25,50,100 mg·kg~(-1)·d~(-1)),卡维地洛10mg·kg~(-1)·d~(-1)灌胃,正常组给予等体积0.9%NaCl腹腔注射,1次/周,共3次;7周末各组大鼠行心脏超声检测心室变化及心功能指标;酶联免疫吸附法(ELISA)检测各组大鼠血清氨基末端脑钠肽前体(N-terminal pro-brain natriuretic peptide,NTproBNP),人基裂解素(human stromelysin-2,ST2)含量;采用原位末端转移酶标记法(TUNEL)染色观察各组大鼠心室肌细胞凋亡情况;蛋白免疫印迹法(Western blot)检测各组大鼠心室肌组织中β_1肾上腺素受体(β_1-AR),蛋白激酶A(protein kinase A,PKA)及钙调素依赖蛋白激酶Ⅱ(CaMK Ⅱ)表达。结果:与正常组比较,模型组大鼠出现心室重构明显及心功能减弱(P<0.01),血清NT-proBNP,ST2含量增多(P<0.01),心室肌细胞凋亡数量增加(P<0.01),心室肌组织中β_1-AR,PKA及CaMK Ⅱ表达增多;与模型组比较,黄芩苷及卡维地洛组大鼠心室重构及心功能改善(P<0.01),血清NT-proBNP,ST2含量降低(P<0.01),心室肌凋亡数量减少(P<0.01),心室肌组织中β_1-AR,PKA及CaMK Ⅱ表达减少(P<0.01)。结论:黄芩苷可有效改善ADR诱导的扩张型心肌病大鼠心室重构,减少心肌细胞凋亡,其机制可能与抑制心室肌细胞β-AR/PKA/CaMK Ⅱ信号通路表达有关。
Objective: To investigate the effect of baicalin on ventricular remodeling, ventricular myocyte apoptosis and β-AR/PKA/CaMK II signaling pathway in rats with dilated cardiomyopathy induced by ADR. Methods: Sixty male Wistar rats were randomly divided into normal group, model group, baicalin low-, medium-, high-dose group, and carvedilol group. The model group was given intraperitoneal injection of ADR 2 mg·kg -1. Baicalin and carvedilol groups were given baicalin (25, 50, 100 mg·kg -1 ·d -1) on the basis of model group, and carvedilol 10 mg·kg -1 ) · d ~ (-1) gavage, the normal group was given an equal volume of 0.9% NaCl intraperitoneal injection, 1 time/week, a total of 3 times; at the end of the 7th week, each group of rats was subjected to echocardiography to detect the changes of the ventricles and cardiac function parameters; The serum N-terminal pro-brain natriuretic peptide (NTproBNP) and human stromelysin-2 (ST2) were detected by immunosorbent assay (ELISA). TUNEL staining was used to observe the apoptosis of ventricular myocytes in each group. β 1 -adrenergic receptor (β 1 -AR) and protein kinase were detected by Western blot in rat ventricular myocytes. Protein kinase A (PKA) and calmodulin-dependent protein kinase II (CaMK II) expression. RESULTS: Compared with the normal group, the rats in the model group had obvious ventricular remodeling and decreased cardiac function (P<0.01), increased NT-proBNP and ST2 levels (P<0.01), and increased the number of ventricular myocyte apoptosis (P< 0.01). The expression of β_1-AR, PKA and CaMK II increased in ventricular myocardium. Compared with the model group, the ventricular remodeling and cardiac function were improved in the baicalin and carvedilol groups (P<0.01). Serum NT-proBNP The content of ST2 decreased (P<0.01), the number of ventricular myocyte apoptosis decreased (P<0.01), and the expression of β_1-AR, PKA and CaMK II decreased in ventricular myocardium (P<0.01). CONCLUSION: Baicalin can effectively improve the ventricular remodeling and reduce myocardial apoptosis in rats with ADR-induced dilated cardiomyopathy. The mechanism may be related to the inhibition of the expression of β-AR/PKA/CaMK II signaling pathway in ventricular myocytes.