C–C Motif chemokine receptor-2 blockade ameliorates pulmonary hypertension in rats and synergizes with a pulmonary vasodilator
Rattachement africain : jp, bg. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
AIMS: We investigated whether the disruption of C-C motif chemokine receptor (CCR) 2 may attenuate the development of pulmonary arterial hypertension (PAH) in any rat models with the reversal of the associated pro-inflammatory state and vascular dysfunction, and synergize with a conventional pulmonary vasodilator. METHODS AND RESULTS: Using Ccr2(-/-) rats generated by CRISPR/Cas9, we investigated pulmonary hypertension (PH) in Ccr2(+/+) or Ccr2(-/-) rats treated with monocrotaline (MCT), SU5416/hypoxia (SuHx) and chronic hypoxia (CH). Ccr2(-/-) decreased the right ventricular systolic pressure, an index of right ventricular hypertrophy and mortality rate, and reversed increased expression of inflammatory cytokines/chemokines [interleukin-6, tumour necrosis factor-α, C-C motif chemokine receptor (CCL)-2, interleukin-1β, transforming growth factor-β] in rats 3weeks after MCT injection, but not in SuHx or CH models. Consistently, Ccr2(-/-) decreased indices of pulmonary vascular diseases (PVDs) and perivascular macrophage infiltration, as well as reversed impaired bone morphogenetic protein receptor type 2 signalling, increased endothelial apoptosis and impaired nitric oxide signalling and decreased phosphodiesterase-5 (PDE5) expression in lungs in MCT-treated rats. Gene expression of receptors for prostaglandin I2 and endothelin was not changed by Ccr2(-/-) in MCT-treated rats. In cultured pulmonary arterial smooth muscle cells (PASMCs), Ccr2(-/-) suppressed CCL2-induced hyperproliferation and dedifferentiation as well as reversed CCL2-induced decrease in PDE5 expression. The whole-genome RNA sequencing analysis identified differentially expressed genes in CCL2-stimulated Ccr2(-/-) PASMCs, which are related to the regulation of cellular differentiation and contraction. Based on studies in rats and cultured PASMCs, we investigated whether a PDE5 inhibitor, tadalafil, synergizes with Ccr2(-/-). Tadalafil administration ameliorated PH and PVDs in MCT-treated Ccr2(-/-) rats but not in Ccr2(+/+) rats. Tadalafil further improved survival in MCT-treated Ccr2(-/-) rats. CONCLUSION: The present findings demonstrated that CCR2 disruption ameliorated PAH in MCT-treated rats, which was associated with the reversal of dysregulated inflammatory pathways and vascular dysfunction and synergized with tadalafil. These findings suggest that CCR2 may be a therapeutic target in intractable PAH patients with a certain CCR2-related inflammatory phenotype and refractory to conventional pulmonary vasodilators.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- C–C Motif chemokine receptor-2 blockade ameliorates pulmonary hypertension in rats and synergizes with a pulmonary vasodilator
- Date Crossref
- 18/11/2024
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Mie University The Department of Pediatrics pays non établi dans la noticeUniversité ou école supérieure
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Nagoya City University The Department of Pediatrics pays non établi dans la noticeUniversité ou école supérieure
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Nagoya City University Hospital pays non établi dans la noticeÉtablissement de santé
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National Heart Hospital The Department of Anesthesiology and Critical Care Lusaka, Zambie (ville ou établissement reconnu, pays non nommé)Établissement de santé
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The University of Osaka pays non établi dans la noticeUniversité ou école supérieure
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Suzuka University of Medical Science The Department of Clinical Engineering pays non établi dans la noticeUniversité ou école supérieure
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Tokyo Medical University pays non établi dans la noticeUniversité ou école supérieure
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The University of Tokyo Laboratory Animal Research Center pays non établi dans la noticeUniversité ou école supérieure
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Osaka University Graduate School of Medicine Institute of Experimental Animal Sciences pays non établi dans la noticeUniversité ou école supérieure
The Department of Pediatrics — Mie University, The Department of Pediatrics — Nagoya City University et Nagoya City University Hospital, avec 6 autres affiliations. Pays d’affiliation : Zambie.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.