Pharmacological Gq inhibition induces strong pulmonary vasorelaxation and reverses pulmonary hypertension.
Gq Inhibition
Pulmonary Arterial Hypertension
Vasoconstriction
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: Germany
ID NLM: 101487380
Informations de publication
Date de publication:
08 Jul 2024
08 Jul 2024
Historique:
received:
23
10
2023
accepted:
05
06
2024
revised:
28
05
2024
medline:
9
7
2024
pubmed:
9
7
2024
entrez:
8
7
2024
Statut:
aheadofprint
Résumé
Pulmonary arterial hypertension (PAH) is a life-threatening disease with limited survival. Herein, we propose the pharmacological inhibition of Gq proteins as a novel concept to counteract pulmonary vasoconstriction and proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in PAH. We demonstrate that the specific pan-Gq inhibitor FR900359 (FR) induced a strong vasorelaxation in large and small pulmonary arteries in mouse, pig, and human subjects ex vivo. Vasorelaxation by FR proved at least as potent as the currently used triple therapy. We also provide in vivo evidence that local pulmonary application of FR prevented right ventricular systolic pressure increase in healthy mice as well as in mice suffering from hypoxia (Hx)-induced pulmonary hypertension (PH). In addition, we demonstrate that chronic application of FR prevented and also reversed Sugen (Su)Hx-induced PH in mice. We also demonstrate that Gq inhibition reduces proliferation and migration of PASMCs in vitro. Thus, our work illustrates a dominant role of Gq proteins for pulmonary vasoconstriction as well as remodeling and proposes direct Gq inhibition as a powerful pharmacological strategy in PH.
Identifiants
pubmed: 38977926
doi: 10.1038/s44321-024-00096-0
pii: 10.1038/s44321-024-00096-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : WE4461/2-1+2
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : FL-276/8-1 and 2
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : INST 213/973-1
Organisme : Innovationsforum
ID : IF-017-22
Informations de copyright
© 2024. The Author(s).
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