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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