Panax ginseng suppresses endothelin-1-induced cardiomyocyte hypertrophy through inhibition of the local angiotensin II-AT1 receptor signaling axis.

Panax ginseng (PG) is a traditional herbal medicine widely used for the treatment of cardiovascular disorders in East Asia. Although PG has been reported to attenuate cardiomyocyte hypertrophy, the molecular mechanisms underlying its cardioprotective effects remain incompletely understood. In this study, we investigated whether modulation of the endothelin-1 (ET-1)-angiotensin II (AngII) signaling axis contributes to the anti-hypertrophic action of PG. Neonatal rat ventricular myocytes (NRVMs) were used to evaluate ET-1-induced hypertrophy, and pharmacological experiments using receptor antagonists were performed to examine the signaling pathways involved. Extracellular AngII levels were quantified by ELISA, intracellular Ca2+ accumulation was assessed in AT1AR-overexpressing NRVMs, and whole-cell patch-clamp recordings were performed in HEK293T cells co-expressing AT1AR and TRPC6. PG significantly attenuated ET-1-induced cardiomyocyte hypertrophy without altering ETAR or ETBR expression. Pharmacological experiments with the ETAR antagonist BQ-123 suggested that the anti-hypertrophic effect of PG could not be explained solely by direct inhibition of ETAR signaling. PG markedly suppressed ET-1-induced extracellular AngII production, and interaction studies with losartan further implicated the AngII-AT1AR pathway in the anti-hypertrophic action of PG. Moreover, PG inhibited AngII-induced intracellular Ca2+ accumulation in AT1AR-overexpressing NRVMs and attenuated AngII-evoked TRPC6-mediated membrane currents without affecting basal channel activity. These findings demonstrate that PG suppresses ET-1-induced cardiomyocyte hypertrophy by inhibiting both ET-1-induced AngII production and downstream AT1AR-dependent signaling, identifying suppression of the AngII-AT1AR signaling axis as a key mechanism underlying its cardioprotective effects.