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Published on: June 3, 2018
Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling
Nicolas G Clavere1, Ali Alqallaf1, Kerry A Rostron2
1Institute of Cardiovascular and Metabolic Research, School of Biological Sciences, Health and Life Sciences Building, University of Reading, Whiteknights, Reading RG6 6UB, UK.
Insights
In progeria, blocking activin A receptor signaling with soluble activin receptor type IIB (sActRIIB) reduced DNA damage and oxidative stress, improving heart function in Ercc1-deficient mice.
Area of Science:
- Cardiovascular biology
- Molecular genetics
- Aging research
Background:
- Cardiac aging involves DNA damage, oxidative stress, fibrosis, and activin signaling pathway activation, leading to dysfunction.
- The role of activin signaling blockade in progeria-induced cardiac effects remains unexplored.
Purpose of the Study:
- To investigate the cardiac effects of progeria induced by attenuated Ercc1 levels.
- To determine the impact of activin signaling blockade using soluble activin receptor type IIB (sActRIIB) on cardiac function and pathology in this model.
Main Methods:
- Induction of progeria in mice by attenuating Ercc1 levels (Ercc1Δ/-).
- Treatment with soluble activin receptor type IIB (sActRIIB).
- Assessment of DNA damage, oxidative stress, cardiac function, cardiomyocyte size, and gene expression via RNA-sequencing.
Main Results:
- Ercc1Δ/- hearts exhibited increased DNA damage and oxidative stress, which were ameliorated by sActRIIB treatment.
- sActRIIB treatment improved cardiac systolic function and induced cardiomyocyte hypertrophy in Ercc1Δ/- hearts.
- RNA-sequencing revealed that sActRIIB reversed pro-oxidant/antioxidant gene expression imbalances and altered hypertrophic gene profiles in Ercc1Δ/- hearts.
Conclusions:
- Inhibition of activin A receptor signaling attenuates cardiac dysfunction, pathological tissue remodeling, and gene expression changes in Ercc1-deficient mice.
- This study identifies activin A receptor signaling as a potential therapeutic target for heart diseases associated with DNA repair deficiencies.
Abstract:
In the heart, ageing is associated with DNA damage, oxidative stress, fibrosis and activation of the activin signalling pathway, leading to cardiac dysfunction. The cardiac effects of activin signalling blockade in progeria are unknown. This study investigated the cardiac effects of progeria induced by attenuated levels of Ercc1, which is required for DNA excision and repair, and the impact of activin signalling blockade using a soluble activin receptor type IIB (sActRIIB). DNA damage and oxidative stress were significantly increased in Ercc1Δ/- hearts, but were reduced by sActRIIB treatment. sActRIIB treatment improved cardiac systolic function and induced cardiomyocyte hypertrophy in Ercc1Δ/- hearts. RNA-sequencing analysis showed that in Ercc1Δ/- hearts, there was an increase in pro-oxidant and a decrease in antioxidant gene expression, whereas sActRIIB treatment reversed this effect. Ercc1Δ/- hearts also expressed higher levels of anti-hypertrophic genes and decreased levels of pro-hypertrophic ones, which were also reversed by sActRIIB treatment. These results show for the first time that inhibition of activin A receptor signalling attenuates cardiac dysfunction, pathological tissue remodelling and gene expression in Ercc1-deficient mice and presents a potentially novel therapeutic target for heart diseases.
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