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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)\u2013angiotensin 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 Ca\n                    <jats:sup>2+<\/jats:sup>\n                    accumulation was assessed in AT\n                    <jats:sub>1A<\/jats:sub>\n                    R-overexpressing NRVMs, and whole-cell patch-clamp recordings were performed in HEK293T cells co-expressing AT\n                    <jats:sub>1A<\/jats:sub>\n                    R and TRPC6. PG significantly attenuated ET-1-induced cardiomyocyte hypertrophy without altering ET\n                    <jats:sub>A<\/jats:sub>\n                    R or ET\n                    <jats:sub>B<\/jats:sub>\n                    R expression. Pharmacological experiments with the ET\n                    <jats:sub>A<\/jats:sub>\n                    R antagonist BQ-123 suggested that the anti-hypertrophic effect of PG could not be explained solely by direct inhibition of ET\n                    <jats:sub>A<\/jats:sub>\n                    R signaling. PG markedly suppressed ET-1-induced extracellular AngII production, and interaction studies with losartan further implicated the AngII\u2013AT\n                    <jats:sub>1A<\/jats:sub>\n                    R pathway in the anti-hypertrophic action of PG. Moreover, PG inhibited AngII-induced intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    accumulation in AT\n                    <jats:sub>1A<\/jats:sub>\n                    R-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 AT\n                    <jats:sub>1A<\/jats:sub>\n                    R-dependent signaling, identifying suppression of the AngII\u2013AT\n                    <jats:sub>1A<\/jats:sub>\n                    R signaling axis as a key mechanism underlying its cardioprotective effects.\n                  <\/jats:p>","DOI":"10.1007\/s00210-026-05979-2","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T09:02:48Z","timestamp":1792486968000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Panax ginseng suppresses endothelin-1-induced cardiomyocyte hypertrophy through inhibition of the local angiotensin II\u2013AT1 receptor signaling axis"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5719-4884","authenticated-orcid":false,"given":"Tomohiro","family":"Numata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Tagashira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Sato-Numata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Takayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoto","family":"Aoyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha Nam","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"5979_CR1","doi-asserted-by":"publisher","first-page":"6073","DOI":"10.1021\/acs.jafc.1c01231","volume":"69","author":"MY Ali","year":"2021","unstructured":"Ali MY, Zaib S, Jannat S, Khan I (2021) Inhibition of angiotensin-I converting enzyme by ginsenosides: structure\u2013activity relationships and inhibitory mechanism. 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