Wnt／β-catenin通路抑制剂Wnt-C59对病理性心肌肥大的治疗作用及其机制

Therapeutic effect of Wnt-C59,a Wnt/β-catenin pathway inhibitor,on pathological cardiac hypertrophy and the underlying mechanism

目的观察Wnt／βcatenin通路抑制剂Wn-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＋wntC59组。（2）细胞实验：使用0．1Mmol／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；④Ang1I＋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、pcatenin核转位、β-catenin下游肥大相关基因C—myc、Cyclin—D1的mRNA表达量。结果WntC59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-rnyc、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 investigate the effect of Wnt-C59, a Wnt/β-catenin pathway inhibitor, on pathological car- diac hypertrophy and its mechanism. Methods ①In the in vivo study, male C57B/L mice （8-10 weeks of age, weight 18-22 g） were performed with transverse aorta constriction （TAC） to induce pathological cardiac hypertro- phy. The mice were randomly divided into sham group, Wnt-C59 group, TAC group and TAC＋Wnt C59 group. ②In the in vitro study, 0.1 μmol/L angiotensin Ⅱ[ （Ang Ⅱ ） was administered to neonatal rat ventricular myocytes （NRVM） for the emergence of pathological cardiac hypertrophy. NRVM were randomly divided into control group, control＋ Wnt-C59 group, Ang 11 group and Ang Ⅱ β-Wnt C59 group. Heart mass/body mass （HM/ BM）, cardiac function and cross-sectional area （CSF） of cardiomyocytes were observed in the in vivo study. The surface area of NRVM, β-catenin nuclear translocation and the mRNA expressions of hypertrophy-related genes C-myc and Cyclin D1 were evaluated in the in vitro study. Results Compared with TAC group, Wnt C59 signifi- cantly reduced the increase of HM/BM [- TAC＋Wnt-C59：（6.02±0.48） vs TAC： （7.45±1.15） rag/g, P〈0.05] and CSF of myocytes induced by TAC, and improved cardiac function [EF： TAC＋ Wnt-C59：（59.29 ± 4.61）% vs TAC： {48.60±2.72} %, P〈0.05]. Compared with Ang Ⅱgroup, Wnvc59 significantly decreased β-catenin nu clear translocation [Ang Ⅱ＋Wnt-C59 ： （ 15.90 ± 4. 11 ） % vs Ang Ⅱ ： （ 25.27 ± 6.69 ） % , P 〈 0.05 ] and mRNA ex- pressions of C rnyc and Cyclin-D1. Conclusion Wnt-C59 exerts therapeutic effect on pathological cardiac hyper- trophy, and its mechanism may be related to the inhibition of β-catenin nuclear translocation and transcription of its downstream hypertrophy genes, Omyc and Cyclin-D1.