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阿托伐他汀对慢性心力衰竭大鼠Hippo-YAP信号通路的调控及其对心室重构的影响

Regulation of atorvastatin on the Hippo-YAP signaling pathway in rats with chronic heart failure and its impact on ventricular remodeling

    摘要
  • 摘要:
    目的 分析阿托伐他汀对慢性心力衰竭(CHF)大鼠Hippo-YAP信号通路的调控及其对心室重构的影响。
    方法 将60只SD大鼠随机分成对照组(给予生理盐水)、模型组(腹腔注射阿霉素，制备CHF大鼠模型)、小剂量组(每天给予阿托伐他汀5.6 mg/kg)、大剂量组(每天给予阿托伐他汀11.2 mg/kg), 每组15只。检测4组大鼠Hippo-YAP信号通路中的YAP、LATS1、LATS2的表达水平。检测4组大鼠左心室组织的纤维化程度。比较4组大鼠左心室射血分数(LVEF)、左心室舒张末期内径(LVEDD)、室间隔厚度(IVST)、左心室心肌质量指数(LVMI)等心脏结构指标，以及血浆N末端脑钠肽前体(NT-proBNP)、基质金属蛋白酶9(MMP-9)、半乳糖凝集素3(Gal-3)水平差异。评估模型组及阿托伐他汀治疗大鼠的YAP、LATS1、LATS2表达水平与心室重塑指标的相关程度。分析上述指标与CHF大鼠心室重构调控的相关性。
    结果 模型组LVEF水平低于对照组, IVST、LVMI和LVEDD水平高于对照组，差异有统计学意义(P < 0.05); 大剂量组、小剂量组LVEF水平高于模型组，且大剂量组高于小剂量组，差异有统计学意义(P < 0.05)。大剂量组、小剂量组IVST、LVMI和LVEDD水平低于模型组，且大剂量组低于小剂量组，差异有统计学意义(P < 0.05)。模型组NT-proBNP、MMP-9和Gal-3水平高于对照组，差异有统计学意义(P < 0.05); 大剂量组、小剂量组NT-proBNP、MMP-9和Gal-3水平低于模型组，且大剂量组低于小剂量组，差异有统计学意义(P < 0.05)。模型组YAP、LATS1、LATS2 mRNA及其蛋白表达水平高于对照组，差异有统计学意义(P < 0.05); 大剂量组、小剂量组YAP、LATS1、LATS2 mRNA及其蛋白表达水平低于模型组，且大剂量组低于小剂量组，差异有统计学意义(P < 0.05)。模型组及阿托伐他汀治疗大鼠的YAP、LATS1、LATS2蛋白表达水平与LVEDD、IVST、LVMI、NT-proBNP、MMP-9及Gal-3呈正相关，与LVEF呈负相关(P < 0.05)。YAP、LATS1、LATS2为CHF大鼠心室重构的负向调控因素，大剂量阿托伐他汀为保护性因素(P < 0.05)。
    结论 阿托伐他汀通过靶向负调控Hippo-YAP信号通路，进而改善CHF心室重构，且其效应呈剂量依赖性。

     

    Abstract:
    Objective To analyze the regulation of atorvastatin on the Hippo-YAP signaling pathway in rats with chronic heart failure (CHF) and its impact on ventricular remodeling.
    Methods Sixty SD rats were randomly divided into control group (administered saline), model group (administered doxorubicin via intraperitoneal injection to establish a CHF model), low-dose group (administered 5.6 mg/kg atorvastatin daily) and high-dose group (administered 11.2 mg/kg atorvastatin daily), with 15 rats in each group. The expression levels of YAP, LATS1and LATS2 in the Hippo-YAP signaling pathway were detected in all four groups. The degree of fibrosis in the left ventricular tissue was also assessed. Comparisons were made among the four groups regarding cardiac structural indicators such as left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), interventricular septal thickness (IVST) and left ventricular mass index (LVMI), as well as plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), matrix metalloproteinase-9 (MMP-9) and galectin-3 (Gal-3). The correlation between the expression levels of YAP, LATS1 as well as LATS2 and ventricular remodeling indicators was evaluated in the model group and atorvastatin-treated rats. The relevance of these indicators to the regulation of ventricular remodeling in CHF rats was analyzed.
    Results The LVEF level in the model group was significantly lower, while IVST, LVMI and LVEDD levels were significantly higher than those in the control group (P < 0.05). The LVEF levels in both the high-dose and low-dose groups were significantly higher than those in the model group, and the high-dose group showed significantly higher LVEF than the low-dose group (P < 0.05). The IVST, LVMI and LVEDD levels in both the high-dose and low-dose groups were significantly lower than those in the model group, and the high-dose group demonstrated significantly lower levels than the low-dose group (P < 0.05). The levels of NT-proBNP, MMP-9 and Gal-3 in the model group were significantly higher than those in the control group (P < 0.05). The levels of NT-proBNP, MMP-9 and Gal-3 in both the high-dose and low-dose groups were significantly lower than those in the model group, and the high-dose group showed significantly lower levels than the low-dose group (P < 0.05). The mRNA expression levels of YAP, LATS1 and LATS2 and their protein in the model group were significantly higher than those in the control group (P < 0.05). The mRNA expression levels of YAP, LATS1 and LATS2 and their protein in both the high-dose and low-dose groups were significantly lower than those in the model group, and the high-dose group demonstrated significantly lower expression levels than the low-dose group (P < 0.05). The protein expression levels of YAP, LATS1 and LATS2 in the model group and atorvastatin-treated rats were positively correlated with LVEDD, IVST, LVMI, NT-proBNP, MMP-9 as well as Gal-3, and negatively correlated with LVEF (P < 0.05). YAP, LATS1 and LATS2 were negative regulatory factors for ventricular remodeling in CHF rats, and high-dose atorvastatin was identified as aprotective factor (P < 0.05).
    Conclusion Atorvastatin improves ventricular remodeling in CHF by negatively regulating HiPO-YAP signaling pathway, and its effect is dose-dependent.

     

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