Simultaneous targeting of oxidative stress and fibrosis reverses cardiomyopathy-induced ventricular remodelling and dysfunction.
Br J Pharmacol
; 178(12): 2424-2442, 2021 06.
Article
en En
| MEDLINE
| ID: mdl-33660265
ABSTRACT
BACKGROUND AND PURPOSE:
Oxidative stress and fibrosis are hallmarks of cardiomyopathy-induced heart failure yet are not effectively targeted by current frontline therapies. Here, the therapeutic effects of the anti-oxidant, N-acetylcysteine (NAC), were compared and combined with an acute heart failure drug with established anti-fibrotic effects, serelaxin (RLX), in a murine model of cardiomyopathy. EXPERIMENTALAPPROACH:
Adult male 129sv mice were subjected to repeated isoprenaline (25 mg·kg-1 )-induced cardiac injury for five consecutive days and then left to undergo fibrotic healing until Day 14. Subgroups of isoprenaline-injured mice were treated with RLX (0.5 mg·kg-1 ·day-1 ), NAC (25 mg·kg-1 ·day-1 ) or both combined, given subcutaneously via osmotic minipumps from Day 7 to 14. Control mice received saline instead of isoprenaline. KEYRESULTS:
Isoprenaline-injured mice showed increased left ventricular (LV) inflammation (~5-fold), oxidative stress (~1-2.5-fold), cardiomyocyte hypertrophy (~25%), cardiac remodelling, fibrosis (~2-2.5-fold) and dysfunction by Day 14 after injury. NAC alone blocked the cardiomyopathy-induced increase in LV superoxide levels, to a greater extent than RLX. Additionally, either treatment alone only partly reduced several measures of LV inflammation, remodelling and fibrosis. In comparison, the combination of RLX and NAC prevented the cardiomyopathy-induced LV macrophage infiltration, remodelling, fibrosis and cardiomyocyte size, to a greater extent than either treatment alone after 7 days. The combination therapy also restored the isoprenaline-induced reduction in LV function, without affecting systolic BP. CONCLUSION AND IMPLICATIONS These findings demonstrated that the simultaneous targeting of oxidative stress and fibrosis is key to treating the pathophysiology and dysfunction induced by cardiomyopathy.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Remodelación Ventricular
/
Cardiomiopatías
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Australia