Formononetin improves heart failure with preserved ejection fraction in mice by activating the PPARa/PGC-1 pathway.

Background: Formononetin (FMN) has beneficial effects in cardiovascular diseases but its functions and mechanisms in heart failure with preserved ejection fraction (HFpEF) remain unclear. This study aimed at determining whether FMN ameliorated HFpEF-induced cardiac dysfunction and exploring its underlying mechanisms. Methods: The mouse model of HFpEF was established through uninephrectomy surgery and d-aldosterone infusion in C57BL/6 mice. Cardiac remodeling and potential mechanisms of FMN in HFpEF were assessed by histological analysis, immunofluorescence, echocardiography, real-time PCR and western blotting sequentially. Results: FMN prevented myocardial dysfunction, fibrosis and cardiomyocyte apoptosis. The mRNA levels of left ventricular hypertrophy markers were increased in HFpEF mice but they remained unchanged in FMN-treated mice. In addition, the expression levels of PPARa and PGC-1 were increased in HFpEF mice for FMN treatment. The PPARa-PGC-1 complex affected the expression of fatty acid content and encoded enzymes in glucose metabolism. Both the hypertrophy and metabolic impairment due to FMN in HFpEF mice were alleviated after the addition of PPARa antagonist GW6471. Conclusion: In conclusion, FMN could prevent the cardiac hypertrophy in HFpEF mice by activating the PPARa/PGC-1 pathway and regulating energy metabolism, which provides a new therapeutic strategy for HFpEF patients. [ABSTRACT FROM AUTHOR]