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Simultaneous targeting of oxidative stress and fibrosis reverses cardiomyopathy‐induced ventricular remodelling and dysfunction
Author(s) -
Wang Chao,
Gaspari Tracey A.,
Ferens Dorota,
Spizzo Iresha,
KempHarper Barbara K.,
Samuel Chrishan S.
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15428
Subject(s) - medicine , isoprenaline , fibrosis , cardiac fibrosis , heart failure , cardiomyopathy , ventricular remodeling , oxidative stress , inflammation , endocrinology , cardiac function curve , myocardial fibrosis , pharmacology , cardiology , stimulation
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. Experimental Approach 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. Key Results 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.

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