C21 preserves endothelial function in the thoracic aorta from DIO mice:role for AT2, Mas and B2 receptors
| Autor: | Marta Gil-Ortega, Beatriz Somoza, María S. Fernández-Alfonso, Marta Viana, M. Paz Lorenzo, Martín Alcalá, Thomas Unger, Raquel González-Blázquez, William A. Boisvert, Ulrike Muscha Steckelings |
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| Přispěvatelé: | Bedrijfsbureau CD, RS: CARIM other |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Receptor Bradykinin B2 Drug Evaluation Preclinical Aorta Thoracic Vasodilation Inbred C57BL Proto-Oncogene Mas Receptors G-Protein-Coupled Renin-Angiotensin System Mice Angiotensin chemistry.chemical_compound Bradykinin B2/metabolism Signal Transduction/drug effects Receptors Proto-Oncogene Proteins c-akt/metabolism Thoracic aorta Thoracic/drug effects Endothelial dysfunction Receptor Aorta Vascular/drug effects Imidazoles/pharmacology Sulfonamides Imidazoles General Medicine Receptor Angiotensin Type 2/agonists Preclinical Aorta Thoracic/drug effects Signal transduction Signal Transduction Type 2/agonists Agonist Endothelium Vascular/drug effects medicine.medical_specialty Nitric Oxide Synthase Type III Sulfonamides/pharmacology medicine.drug_class Bradykinin Thiophenes/pharmacology Thiophenes Diet High-Fat Nitric Oxide Cyclic AMP-Dependent Protein Kinases/metabolism Receptor Angiotensin Type 2 Proto-Oncogene Proteins medicine.artery Internal medicine Human Umbilical Vein Endothelial Cells medicine Animals Humans Endothelium Obesity Vascular Diseases Receptor Bradykinin B2/metabolism Protein kinase B G-Protein-Coupled/metabolism Vascular Diseases/etiology Nitric Oxide Synthase Type III/metabolism Receptor Cross-Talk Receptors G-Protein-Coupled/metabolism Proto-Oncogene Proteins/metabolism medicine.disease Cyclic AMP-Dependent Protein Kinases Diet Mice Inbred C57BL High-Fat Endocrinology chemistry Renin-Angiotensin System/drug effects Nitric Oxide/metabolism Drug Evaluation Endothelium Vascular Obesity/complications Proto-Oncogene Proteins c-akt |
| Zdroj: | González-Blázquez, R, Alcalá, M, Fernández-Alfonso, M S, Steckelings, U M, Lorenzo, M P, Viana, M, Boisvert, W, Unger, T, Ortega, M G & Somoza, B 2021, ' C21 preserves endothelial function in the thoracic aorta from DIO mice : role for AT2, Mas and B2 receptors ', Clinical Science, vol. 135, no. 9, pp. 1145-1163 . https://doi.org/10.1042/CS20210049 Clinical Science, 135(9), 1145-1163. Portland Press Ltd. |
| ISSN: | 0143-5221 |
| DOI: | 10.1042/CS20210049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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