Gut microbiota-derived isoxanthohumol metabolite, 8-prenylnaringenin, mitigates endothelial dysfunction in Angiotensin II-induced hypertension through G protein-coupled estrogen receptor-mediated eNOS activation.
| Title: | Gut microbiota-derived isoxanthohumol metabolite, 8-prenylnaringenin, mitigates endothelial dysfunction in Angiotensin II-induced hypertension through G protein-coupled estrogen receptor-mediated eNOS activation. |
|---|---|
| Authors: | Lee SY; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.; Ngoc Bui AT; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.; Thai TN; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.; Lee GH; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.; Kim M; Department of Sport Science, Chungnam National University, Daejeon 34141, South Korea.; Kim SY; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.; Maeng J; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.; Jung JK; College of Pharmacy, Chungbuk National University, Cheongju 28160, South Korea.; Lee MY; College of Pharmacy, Dongguk University, Gyeonggi-do 10326, South Korea.; Lee SK; Department of Sport Science, Chungnam National University, Daejeon 34141, South Korea.; Yun HY; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.; Kim ND; CoBX Bio Inc., Seoul 08590, South Korea.; Han EH; Drug & Disease Target Research Team, Division of Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Cheongju 28119, South Korea.; Jeong HG; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea. Electronic address: hgjeong@cnu.ac.kr. |
| Source: | Biochemical pharmacology [Biochem Pharmacol] 2026 Apr; Vol. 246, pp. 117728. Date of Electronic Publication: 2026 Jan 20. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Elsevier Science; Original Publication: Oxford, New York [etc.] Paragamon Press. |
| MeSH Terms: | Nitric Oxide Synthase Type III*/metabolism ; Angiotensin II*/toxicity ; Gastrointestinal Microbiome*/physiology ; Gastrointestinal Microbiome*/drug effects ; Hypertension*/chemically induced ; Hypertension*/metabolism ; Hypertension*/drug therapy ; Flavanones*/pharmacology ; Flavanones*/metabolism ; Flavanones*/therapeutic use ; Endothelium, Vascular*/drug effects ; Endothelium, Vascular*/metabolism ; Receptors, G-Protein-Coupled*/metabolism ; Receptors, Estrogen*/metabolism ; Xanthones*/metabolism; Enzyme Activation/drug effects ; Enzyme Activation/physiology ; Animals ; Mice ; Mice, Inbred C57BL ; Male ; Humans |
| 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.; (Copyright © 2026. Published by Elsevier Inc.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: 8-Prenylnaringenin; Angiotensin II; Endothelial dysfunction; Endothelial nitric oxide synthase; G-protein-coupledestrogen receptor; Hypertension; Vasorelaxation |
| Substance Nomenclature: | EC 1.14.13.39 (Nitric Oxide Synthase Type III); 11128-99-7 (Angiotensin II); 0 (8-prenylnaringenin); 0 (Flavanones); 0 (Receptors, G-Protein-Coupled); 0 (Receptors, Estrogen); 0 (Xanthones); EC 1.14.13.39 (Nos3 protein, mouse); 0 (isoxanthohumol) |
| Entry Date(s): | Date Created: 20260122 Date Completed: 20260219 Latest Revision: 20260219 |
| Update Code: | 20260220 |
| DOI: | 10.1016/j.bcp.2026.117728 |
| PMID: | 41571201 |
| Database: | MEDLINE |
Journal Article