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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Simultaneous targeting of oxidative stress and fibrosis reverses cardiomyopathy-induced ventricular remodelling and
Chao Wang1, Tracey A Gaspari1, Dorota Ferens1
1Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
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.
Insights
Combining N-acetylcysteine (NAC) and serelaxin (RLX) effectively treats cardiomyopathy by targeting oxidative stress and fibrosis. This combination therapy improved cardiac function and reduced inflammation and remodeling in mice.
Area of Science:
- Cardiology
- Pharmacology
- Biomedical Science
Background:
- Cardiomyopathy-induced heart failure is characterized by oxidative stress and fibrosis.
- Current therapies do not effectively target these pathological mechanisms.
- N-acetylcysteine (NAC) is an antioxidant, and serelaxin (RLX) has anti-fibrotic effects.
Purpose of the Study:
- To compare the therapeutic effects of NAC and RLX individually and in combination.
- To evaluate their efficacy in a murine model of cardiomyopathy.
- To determine if combined targeting of oxidative stress and fibrosis improves cardiac function.
Main Methods:
- Adult male mice were subjected to isoprenaline-induced cardiac injury.
- Mice received treatments of RLX, NAC, or both via osmotic minipumps from Day 7 to 14 post-injury.
- Cardiac function, inflammation, oxidative stress, remodelling, and fibrosis were assessed.
Main Results:
- Isoprenaline injury increased LV inflammation, oxidative stress, hypertrophy, remodelling, fibrosis, and dysfunction.
- NAC alone reduced LV superoxide levels more effectively than RLX.
- Combined RLX and NAC treatment prevented LV macrophage infiltration, remodelling, fibrosis, and cardiomyocyte size increase, and restored LV function.
Conclusions:
- Simultaneous targeting of oxidative stress and fibrosis is crucial for treating cardiomyopathy.
- Combination therapy with RLX and NAC demonstrates superior efficacy compared to monotherapy.
- This approach offers a promising strategy for managing cardiomyopathy-induced heart failure.
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