Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis
| Autor: | Bruce, E, Shenoy, V, Rathinasabapathy, A, Espejo, A, Horowitz, A, Oswalt, A, Francis, J, Nair, A, Unger, T, Raizada, M K, Steckelings, Ulrike Muscha, Sumners, C, Katovich, M J |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Myocardium/metabolism Pyridines Angiotensin II Type 2 Receptor Blockers/pharmacology Hypertension Pulmonary Pulmonary Fibrosis Ventricular Dysfunction Right Proto-Oncogene Proteins/antagonists & inhibitors Ventricular Remodeling/drug effects Angiotensin II Type 2 Receptor Blockers Vascular Remodeling Proto-Oncogene Mas Receptor Angiotensin Type 2 Receptors G-Protein-Coupled Rats Sprague-Dawley Signal Transduction/drug effects Proto-Oncogene Proteins Animals Angiotensin II/analogs & derivatives Ventricular Dysfunction Right/chemically induced Lung Imidazoles/pharmacology Pyridines/pharmacology Receptors G-Protein-Coupled/antagonists & inhibitors Peptide Fragments/pharmacology Monocrotaline Lung/drug effects Hypertrophy Right Ventricular Ventricular Remodeling Angiotensin II Myocardium Ventricular Function Right/drug effects Hemodynamics Imidazoles Pulmonary Fibrosis/chemically induced Hypertrophy Right Ventricular/chemically induced Cardiovascular Agents Receptor Angiotensin Type 2/agonists Research Papers Fibrosis Peptide Fragments Disease Models Animal Hemodynamics/drug effects Cardiovascular Agents/pharmacology Hypertension Pulmonary/chemically induced Ventricular Function Right Vascular Remodeling/drug effects Signal Transduction |
| Zdroj: | Bruce, E, Shenoy, V, Rathinasabapathy, A, Espejo, A, Horowitz, A, Oswalt, A, Francis, J, Nair, A, Unger, T, Raizada, M K, Steckelings, U M, Sumners, C & Katovich, M J 2015, ' Selective activation of angiotensin AT 2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis ', British Journal of Pharmacology, vol. 172, no. 9, pp. 2219-2231 . https://doi.org/10.1111/bph.13044 |
| DOI: | 10.1111/bph.13044 |
| Popis: | Background and Purpose Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right-heart failure and death. A dys-regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT 2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT 2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH. Experimental Approach A single s.c. injection of MCT (50 mg·kg -1) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg·kg -1 C21, 3 mg·kg -1 PD-123319 or 0.5 mg·kg -1 A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses. Key Results Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co-administration of the AT 2 receptor antagonist, PD-123319, or the Mas antagonist, A779, abolished the protective actions of C21. Conclusions and Implications Taken together, our results suggest that the AT 2 receptor agonist, C21, may hold promise for patients with PH. |
| Databáze: | OpenAIRE |
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