Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling

Abstract

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.