Abstract
BACKGROUND: Mitochondrial dysfunction and oxidative stress are central to the development of cardiac hypertrophy and heart failure. Panax ginseng (PG), a principal herb used in Kampo medicine, has been reported to exert cardioprotective effects; however, its intracellular actions under endothelin-1 (ET-1)- and β-adrenergic stress remain incompletely defined. PURPOSE: To determine whether a standardized PG extract attenuates cardiac hypertrophy and whether its effects are associated with mitochondrial function and Ca(2+)-reactive oxygen species (ROS) homeostasis in complementary cellular and in vivo stress models. METHODS: Neonatal rat ventricular myocytes (NRVMs) were exposed to ET-1 to induce hypertrophy and mitochondrial fragmentation. Mitochondrial morphology, intracellular Ca²⁺, ROS, and adenosine triphosphate (ATP) levels were quantified by fluorescence imaging and biochemical assays. In mice, isoproterenol (ISO) was administered for 14 days to induce cardiac stress; PG was given orally. Cardiac structure and function were evaluated by histology and echocardiography. Expression of mitochondrial fusion/fission markers was analyzed. All experiments used predefined exclusion criteria and blinded analyses. RESULTS: PG was associated with reduced ET-1-induced hypertrophy in a concentration-dependent manner (IC(50) = 7.5 µg/mL), was associated with reduced mitochondrial fragmentation and loss of membrane potential, preserved ATP levels, and mitigated increases in intracellular Ca(2+) and ROS in NRVMs. In ISO-treated mice, oral PG (50 mg/kg/day for 14 days) improved systolic function, limited hypertrophic remodeling, and reduced interstitial fibrosis. CONCLUSION: PG exhibits pharmacological cardioprotection associated with modulation of mitochondrial dynamics and attenuation of cellular stress responses. These findings support further investigation of PG as a mitochondria-engaging natural product with the potential to mitigate pathological cardiac remodeling and heart failure progression.