2. Academic Validation
  3. Gut microbiota-derived isoxanthohumol metabolite, 8-prenylnaringenin, mitigates endothelial dysfunction in Angiotensin II-induced hypertension through G protein-coupled estrogen receptor-mediated eNOS activation

Gut microbiota-derived isoxanthohumol metabolite, 8-prenylnaringenin, mitigates endothelial dysfunction in Angiotensin II-induced hypertension through G protein-coupled estrogen receptor-mediated eNOS activation

  • Biochem Pharmacol. 2026 Apr:246:117728. doi: 10.1016/j.bcp.2026.117728.
Seung Yeon Lee 1,  Anh Thi Ngoc Bui 1,  Tuyet Ngan Thai 1,  Gi Ho Lee 1,  Minseo Kim 2,  Su Yeon Kim 1,  Jeonghwan Maeng 1,  Jae-Kyung Jung 3,  Moo-Yeol Lee 4,  Sang Ki Lee 2,  Hwi-Yeol Yun 1,  Nam Doo Kim 5,  Eun Hee Han 6,  Hye Gwang Jeong 7
Affiliations

Affiliations

  • 1 College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.
  • 2 Department of Sport Science, Chungnam National University, Daejeon 34141, South Korea.
  • 3 College of Pharmacy, Chungbuk National University, Cheongju 28160, South Korea.
  • 4 College of Pharmacy, Dongguk University, Gyeonggi-do 10326, South Korea.
  • 5 CoBX Bio Inc., Seoul 08590, South Korea.
  • 6 Drug & Disease Target Research Team, Division of Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Cheongju 28119, South Korea.
  • 7 College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea. Electronic address: [email protected].
PMID: 41571201 DOI: 10.1016/j.bcp.2026.117728
Abstract

Humulus lupulus L. (hops), which is traditionally used in brewing, is a rich botanical source of prenylated Flavonoids with potential cardiovascular protective properties. Of these, 8-prenylnaringenin (8-PN), a potent phytoestrogen formed from isoxanthohumol by the gut microbiota, has been implicated in vascular health. Nitric oxide (NO), which is produced by endothelial nitric oxide synthase (eNOS), exerts profound effects on vascular tone and endothelial integrity. This study examined the protective effects of 8-PN on endothelial signaling and vascular function using in vitro endothelial cell assays, ex vivo isolated artery preparations, and an in vivo mouse model of Angiotensin II (Ang II)-induced endothelial dysfunction. In endothelial cells, 8-PN increased phosphorylation of eNOS on Ser1177 and NO production through G-protein coupled Estrogen receptor (GPER)-mediated CA2+-dependent signaling pathways involving phosphorylation of CA2+/calmodulin-dependent protein kinase β (CaMKKβ) and AMPK-activated protein kinase (AMPK). Furthermore, 8-PN activated eNOS via GPER-mediated epidermal growth factor receptor (EGFR) activation, with c-Src facilitating phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-related kinase (ERK) phosphorylation. Molecular docking results indicated that 8-PN could bind to GPER and facilitate the activation of downstream signaling cascades. Both of 8-PN-mediated eNOS phosphorylation are mediated through the Gβγ subunit. In vivo, 8-PN attenuated angiotensin II-induced endothelial dysfunction in mice and induced vasorelaxation in vivo. 8-PN stimulated eNOS phosphorylation and NO production via dual GPER-dependent pathways, supporting its potential as a therapeutic candidate for endothelial dysfunction-related vascular diseases.

Keywords

8-Prenylnaringenin; Angiotensin II; Endothelial dysfunction; Endothelial nitric oxide synthase; G-protein-coupledestrogen receptor; Hypertension; Vasorelaxation.

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