Cardioprotective Role of 5,7,4′‐Trimethoxy Flavanone Through PI3K/AKT‐Nrf2 Signaling in Mice

Myocardial hypertrophy represents a pathological cardiac adaptation involving abnormal cardiomyocyte enlargement that compromises ventricular function and precipitates heart failure. The flavonoid compound 5,7,4'-trimethoxy flavanone exhibits significant anti-inflammatory and antioxidant activities, highlighting its potential as a phytocompound with desired pharmacological value for managing hypertrophic cardiac conditions. This investigation examined the cardioprotective effects of 5,7,4'-trimethoxy flavanone against isoproterenol-induced myocardial hypertrophy in Swiss albino mouse models. Treatment with this flavonoid significantly reduced cardiac mass and myocyte diameter. As a result, expression levels of hypertrophic biomarkers such as ANP, BNP, calcineurin, and GATA4 in isoproterenol-challenged animals were also markedly decreased. Additionally, 5,7,4'-trimethoxy flavanone administration diminished expression of oxidative stress markers and inhibited myocardial fibrosis development, as confirmed through Masson's trichrome histological evaluation. This mechanistic investigation revealed that this compound downregulated PI3K/AKT signaling proteins while enhancing Nrf2-mediated antioxidant pathways. These molecular effects resulted in inhibition of apoptosis and enhanced cellular survival, marked by elevated Bcl-2 and Bcl-xL expression, as well as reduced caspase-3 enzymatic activity and decreased TUNEL-positive cardiomyocytes. The experimental evidence supports the potential of 5,7,4'-trimethoxy flavanone as an effective adjunct for cardiac hypertrophy through its dual modulation of PI3K/AKT and Nrf2 signaling networks. These findings establish 5,7,4'-trimethoxy flavanone as a promising cardioprotective agent, warranting further clinical development for hypertrophic cardiomyopathy treatment strategies.