Targeting 5-Hydroxytryptamine Receptor 1A in the Portal Vein to Decrease Portal Hypertension

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Grant support

This work was supported by the National Natural Science Foundation of China (82030021 to Wei-Fen Xie, 81900543 to Chang-Peng Zhu, and 82200678 to Ke-Qi Wang) , the National Key R&D Program of China (2023YFC2507500 to Wei-Fen Xie) , the Instituto de Salud Carlos III (FIS PI23/00945 and DTS22/00010 to Jordi Gracia-Sancho, cofunded by the European Union) , and AGAUR-Generalitat de Catalunya (2021 SGR 01322 and 2021 PROD 00036 to Jordi Gracia-Sancho) .

Análisis de autorías institucional

Aristu-Zabalza, PeioAutor o CoautorGracia-Sancho, JordiAutor (correspondencia)

6 de octubre de 2024

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Artículo

Publicado en:Gastroenterology. 167 (5): 993-1007 - 2024-10-01 167(5), DOI: 10.1053/j.gastro.2024.06.007

Autores: Zhu, CP; Liu, SQ; Wang, KQ; Xiong, HL; Feng, JF; Zhang, X; Xie, WF; Aristu-Zabalza, P; Boyer-Diaz, Z; Gracia-Sancho, J; Song, SH; Luo, C; Chen, WS; Dong, WH

Afiliaciones

Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Key Lab Receptor Res,State Key Lab Drug Res, Shanghai, Peoples R China - Autor o Coautor

IDIBAPS Hosp Clin Barcelona, CIBEREHD, Liver Vasc Biol Res Grp, Barcelona, Spain - Autor o Coautor

Naval Med Univ, Changzheng Hosp, Dept Gastroenterol, 415 Fengyang Rd, Shanghai, Peoples R China - Autor o Coautor

Naval Med Univ, Changzheng Hosp, Dept Intervent Radiol, 415 Fengyang Rd, Shanghai, Peoples R China - Autor o Coautor

Naval Med Univ, Changzheng Hosp, Dept Pharm, Shanghai, Peoples R China - Autor o Coautor

Naval Med Univ, Changzheng Hosp, Organ Transplantat Ctr, Shanghai, Peoples R China - Autor o Coautor

Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China - Autor o Coautor

Univ Bern, Dept BioMed Res, Hepatol, Bern, Switzerland - Autor o Coautor

Resumen

BACKGROUND & AIMS:Portal hypertension (PH) is one of themost frequent complications of chronic liver disease. The pe-ripheral 5-hydroxytryptamine (5-HT) level was increased incirrhotic patients. We aimed to elucidate the function andmechanism of 5-HT receptor 1A (HTR1A) in the portal vein(PV) on PH.METHODS:PH models were induced by thio-acetamide injection, bile duct ligation, or partial PV ligation.HTR1A expression was detected using real-time polymerasechain reaction, in situ hybridization, and immunofluorescencestaining. In situ intraportal infusion was used to assess theeffects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1Aantagonist WAY-100635 on portal pressure (PP).Htr1a-knockout (Htr1a(-/-)) rats and vascular smooth muscle cell(VSMC)-specificHtr1a-knockout (Htr1a(Delta VSMC)) mice were usedto confirm the regulatory role of HTR1A on PP.RESULTS:HTR1A expression was significantly increased in the hyper-tensive PV of PH model rats and cirrhotic patients. Additionally,8-OH-DPAT increased, but WAY-100635 decreased, the PP inrats without affecting liverfibrosis and systemic hemody-namics. Furthermore, 5-HT or 8-OH-DPAT directly induced thecontraction of isolated PVs. Genetic deletion ofHtr1ain ratsand VSMC-specificHtr1aknockout in mice prevented thedevelopment of PH. Moreover, 5-HT triggered adenosine 30,50-cyclic monophosphate pathway-mediated PV smooth musclecell contraction via HTR1A in the PV. We also confirmedalverine as an HTR1A antagonist and demonstrated its capacityto decrease PP in rats with thioacetamide-, bile duct ligation-,and partial PV ligation-induced PH.CONCLUSIONS:Ourfind-ings reveal that 5-HT promotes PH by inducing the contractionof the PV and identify HTR1A as a promising therapeutic targetfor attenuating PH. As an HTR1A antagonist, alverine is ex-pected to become a candidate for clinical PH treatment.

Palabras clave

2 dipropylamino 8 hydroxytetralin5-hydroxytryptamine8-hydroxy-2-(di-n-propylamino)tetralinAlverinAlverineAlverine citrateAnimalAnimalsC57bl mouseCirrhosisCyclic ampDisease modelDisease models, animalDrug effectEtiologyExperimental liver cirrhosisGeneticsHtr1aHuman tissueHumansHypertension, portalImmunofluorescenceImmunofluorescence assayImmunohistochemistryIn situ hybridizationInternational unionIntraportal drug administrationIrritable-bowel-syndromeKetanseriKnockout mouseLigationLight-chain kinaseLiver cirrhosisLiver cirrhosis, experimentalLiver fibrosisLiver tissueMaleMechanismsMessenger rnaMetabolismMiceMice, inbred c57blMice, knockoutMouseMuscle fiber contractionMuscle, smooth, vascularMyocytes, smooth muscleN [2 [4 (2 methoxyphenyl) 1 piperazinyl]ethyl] n (2 pyridyl)cyclohexanecarboxamideN-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-n-(2-pyridinyl)cyclohexanecarboxamideNonhumanPathologyPathophysiologyPhPhosphorylationPiperazine derivativePiperazinesPortal hypertensionPortal pressurePortal veinPortal vein blood pressurePortal vein smooth muscle cellsPressurePyridine derivativePyridinesRatRatsRats, sprague-dawleyReal time polymerase chain reactionReceptor, serotonin, 5-ht1aSerotoninSerotonin 1 agonistSerotonin 1 receptorSerotonin 5-ht1 receptor agonistsSerotonin 5-ht1 receptor antagonistsSignal transductionSmooth muscle cellSprague dawley ratThioacetamideVascular smooth muscleVascular smooth muscle cellVascular smooth-muscleVenous smooth muscleWestern blotting

Indicios de calidad

Impacto bibliométrico. Análisis de la aportación y canal de difusión

El trabajo ha sido publicado en la revista GASTROENTEROLOGY debido a la progresión y el buen impacto que ha alcanzado en los últimos años, según la agencia WoS (JCR), se ha convertido en una referencia en su campo. En el año de publicación del trabajo, 2024 aún no existen indicios calculados, pero en 2023, se encontraba en la posición 4/143, consiguiendo con ello situarse como revista Q1 (Primer Cuartil), en la categoría Gastroenterology & Hepatology. Destacable, igualmente, el hecho de que la Revista está posicionada por encima del Percentil 90.

Impacto y visibilidad social

Análisis de liderazgo de los autores institucionales

Este trabajo se ha realizado con colaboración internacional, concretamente con investigadores de: China; Switzerland.