C21 preserves endothelial function in the thoracic aorta from DIO mice: role for AT2, Mas and B2 receptors.
Clin Sci (Lond)
; 135(9): 1145-1163, 2021 05 14.
Article
em En
| MEDLINE
| ID: mdl-33899912
ABSTRACT
Compound 21 (C21), a selective agonist of angiotensin II type 2 receptor (AT2R), induces vasodilation through NO release. Since AT2R seems to be overexpressed in obesity, we hypothesize that C21 prevents the development of obesity-related vascular alterations. The main goal of the present study was to assess the effect of C21 on thoracic aorta endothelial function in a model of diet-induced obesity (DIO) and to elucidate the potential cross-talk among AT2R, Mas receptor (MasR) and/or bradykinin type 2 receptor (B2R) in this response. Five-week-old male C57BL6J mice were fed a standard (CHOW) or a high-fat diet (HF) for 6 weeks and treated daily with C21 (1 mg/kg p.o) or vehicle, generating four groups CHOW-C, CHOW-C21, HF-C, HF-C21. Vascular reactivity experiments were performed in thoracic aorta rings. Human endothelial cells (HECs; EA.hy926) were used to elucidate the signaling pathways, both at receptor and intracellular levels. Arteries from HF mice exhibited increased contractions to Ang II than CHOW mice, effect that was prevented by C21. PD123177, A779 and HOE-140 (AT2R, Mas and B2R antagonists) significantly enhanced Ang II-induced contractions in CHOW but not in HF-C rings, suggesting a lack of functionality of those receptors in obesity. C21 prevented those alterations and favored the formation of AT2R/MasR and MasR/B2R heterodimers. HF mice also exhibited impaired relaxations to acetylcholine (ACh) due to a reduced NO availability. C21 preserved NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways. In conclusion, C21 favors the interaction among AT2R, MasR and B2R and prevents the development of obesity-induced endothelial dysfunction by stimulating NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Tiofenos
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Doenças Vasculares
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Endotélio Vascular
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Proteínas Proto-Oncogênicas
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Receptores Acoplados a Proteínas G
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Receptor Tipo 2 de Angiotensina
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Receptor B2 da Bradicinina
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Imidazóis
Tipo de estudo:
Etiology_studies
Idioma:
En
Revista:
Clin Sci (Lond)
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Espanha