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目的观察Wnt/β-catenin通路抑制剂Wnt-C59对病理性心肌肥大的作用并探讨这一过程的分子机制。方法 (1)动物实验:对8~10周龄(18~22g)的雄性C57B/L小鼠施行主动脉缩窄术(TAC)以诱导病理性心肌肥大。实验分4组:1对照组;2Wnt-C59组;3TAC模型组;4TAC+Wnt-C59组。(2)细胞实验:使用0.1μmol/L血管紧张素Ⅱ(AngⅡ)刺激新生大鼠心肌细胞(NRVM)诱导病理性心肌细胞肥大。实验分4组:1对照组;2Wnt-C59组;3AngⅡ模型组;4AngⅡ+Wnt-C59组。观察的实验指标:TAC术后4周小鼠的心脏质量/体质量、心功能、心肌细胞横截面面积;NRVM表面积、β-catenin核转位、β-catenin下游肥大相关基因C-myc、Cyclin-D1的mRNA表达量。结果 Wnt-C59明显降低由TAC所致的心脏质量/体质量增加[TAC+Wnt-C59:(6.02±0.48)比TAC:(7.45±1.15)mg/g,P<0.05],改善心功能[射血分数:TAC+Wnt-C59:(59.29±4.61)%比TAC:(48.60±2.72)%,P<0.05]。并减轻TAC诱导的心肌细胞横截面积增加。Wnt-C59明显减轻AngⅡ诱导的心肌细胞表面积增大,β-catenin入核[AngⅡ+Wnt-C59:(15.90±4.11)%比AngⅡ(25.27±6.69)%,P<0.05]以及肥大基因C-myc、Cyclin-D1的高表达。结论 Wnt/β-catenin通路抑制剂Wnt-C59对病理性心肌细胞肥大具有保护作用,其机制可能是抑制β-catenin入核进而抑制其下游肥大基因C-myc、Cyclin-D1的转录。
Objective To observe the effect of Wnt / β-catenin pathway inhibitor Wnt-C59 on pathological myocardial hypertrophy and to explore the molecular mechanism of this process. Methods (1) Animal Experiments: Aortic constriction (TAC) was performed on male C57B / L mice aged 8-10 weeks (18-22 g) to induce pathological cardiac hypertrophy. The experiment was divided into 4 groups: 1 control group; 2Wnt-C59 group; 3TAC model group; 4TAC + Wnt-C59 group. (2) Cell experiment: Neonatal rat cardiomyocytes (NRVM) were stimulated to induce pathological cardiomyocyte hypertrophy by 0.1μmol / L AngⅡ. The experiment was divided into 4 groups: 1 control group; 2Wnt-C59 group; 3AngⅡ model group; 4AngⅡ + Wnt-C59 group. The experimental indexes of observation: heart mass / body weight, cardiac function and myocardial cell cross-sectional area of mice at 4 weeks after TAC; NRVM surface area, β-catenin nuclear translocation, C-myc, Cyclin -D1 mRNA expression level. Results Wnt-C59 significantly decreased cardiac mass / body mass gain due to TAC [TAC + Wnt-C59: (6.02 ± 0.48) vs TAC: (7.45 ± 1.15) mg / g, P < Ejection fraction: TAC + Wnt-C59: (59.29 ± 4.61)% vs. TAC: (48.60 ± 2.72)%, P <0.05]. And reduce the TAC-induced increase in cardiac myocyte cross-sectional area. Cys: (15.90 ± 4.11)% vs AngⅡ (25.27 ± 6.69)%, P <0.05], and the gene expression of C-catenin in the nucleus was significantly decreased by Wnt-C59 compared with AngⅡ myc, Cyclin-D1 high expression. Conclusion The Wnt / C-catenin pathway inhibitor Wnt-C59 can protect the pathological myocyte hypertrophy by inhibiting the entry of β-catenin into the nucleus and inhibiting the transcription of C-myc and Cyclin-D1.