Andrographolide mitigates salt-sensitive cardiac remodelling by regulating mitochondrial stress and apoptosis-related transcriptional responses: Experimental and computational evidence

Introduction Cardiac hypertrophy is a major precursor of heart failure and is closely associated with mitochondrial dysfunction. Although andrographolide has demonstrated cardioprotective properties, its effects on mitochondrial quality control (MQC) during hypertensive cardiac remodelling remain unclear. This study investigated whether andrographolide attenuates salt-sensitive cardiac hypertrophy by modulating MQC and apoptosis-associated signalling in a uninephrectomy-deoxycorticosterone acetate-salt (UNX-DOCA-salt) rat model. Material and Methods Male Sprague-Dawley rats subjected to the UNX-DOCA-salt model were treated with andrographolide or spironolactone. Cardiac hypertrophy was assessed by cardiac weight, cardiac weight-to-body weight ratio, and cardiomyocyte cross-sectional area. Mitochondrial function was evaluated by succinate dehydrogenase activity, mitochondrial calcium concentration, and mitochondrial DNA copy number, while the expression of hypertrophy-, MQC-, and apoptosis-related genes was quantified by RT-qPCR. Partial least squares regression (PLS-R), correlation analysis, molecular docking, and MM/GB(PB)SA were performed to identify and computationally validate key molecular determinants. Results UNX-DOCA-salt induced marked cardiac hypertrophy, mitochondrial dysfunction, and upregulation of DRP1, PINK1, PGC-1α, TFAM, p53, and BNP. Among the tested doses, andrographolide at 30 mg/kg body weight more consistently restored structural, mitochondrial, and molecular alterations than 60 mg/kg body weight. Multivariate analysis identified DRP1 as the principal molecular determinant associated with hypertrophic remodeling, whereas molecular docking and MM/GB(PB)SA demonstrated energetically favorable interactions of andrographolide within the DRP1 GTPase-binding region. Discussion These findings suggest that andrographolide attenuates salt-sensitive cardiac hypertrophy, at least in part, through modulation of mitochondrial homeostasis. DRP1-mediated mitochondrial dynamics may represent a promising therapeutic target underlying the cardioprotective effects of andrographolide in hypertensive cardiac remodeling.