Polydatin Attenuates Isoproterenol Induced Cardiac Hypertrophy in Association with Reduced Oxidative Stress, NOX2 Subunit Expression, and CaMKII-MEF2C Signaling

Pathological cardiac hypertrophy induced by chronic β-adrenergic receptor (β-AR) stimulation contributes to adverse cardiac remodeling and the progression of heart failure, with NADPH oxidase (NOX2)-derived reactive oxygen species (ROS) acting as key mediators of redox-dependent hypertrophic signaling. Sustained ROS generation can promote oxidative activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and downstream myocyte enhancer factor 2 C (MEF2C)-mediated transcriptional reprogramming. Polydatin, a natural glucoside of resveratrol, has been reported to exert antioxidant and cardioprotective effects. However, its influence on the NOX2–ROS–CaMKII–MEF2C axis under chronic β-AR stimulation remains unclear. In the present study, male Wistar rats were assigned to control, isoproterenol (5 mg/kg/day, subcutaneous, 4 weeks), or isoproterenol + polydatin (100 mg/kg/day, oral gavage) groups. Cardiac hypertrophy was evaluated by morphometric indices, ANP and BNP mRNA expression levels, and histological analyses. Oxidative stress was assessed through NADH oxidase activity, protein carbonyl content, and total antioxidant status. Protein expression of NOX2 subunits (gp91phox, p22phox, p47phox, p67phox, p40phox) and components of the CaMKII–MEF2C pathway were determined by Western blot and reverse transcription quantitative PCR (RT–qPCR). Isoproterenol administration induced marked cardiac hypertrophy, elevated oxidative stress markers, increased expression of NOX2 regulatory subunits, and activated the CaMKII–MEF2C pathway. Polydatin treatment significantly attenuated hypertrophic indices, reduced NADH oxidase activity and protein carbonyl levels, restored antioxidant capacity, and suppressed p47phox, p67phox, p40phox expression along with p-CaMKII Thr286 /CaMKII, ox-CaMKII/CaMKII ratios and MEF2C expression. These findings suggest that the attenuation of isoproterenol induced cardiac hypertrophy by polydatin is associated with modulation of oxidative stress, NOX2 subunit expression, and CaMKII–MEF2C signaling, although a causal role of this pathway remains to be established.