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• W3107007605 abstract "Abstract Introduction In the heart, ageing is associated with pathological remodelling due to an increase of DNA damage, oxidative stress and fibrosis that impairs function, often leading to heart failure. Ageing is also associated with activation of the activin signalling pathway which contributes to cardiac dysfunction. Previous studies have shown that inhibition of the activin signalling pathway preserves cardiac function during aging. However, the beneficial effects of this inhibition in cardiac disorders such as accelerated ageing remain unknown. Purpose We hypothesized that inhibition of the activin receptor would be beneficial for the pathological cardiac phenotype of the Ercc1Δ/− mouse model of accelerated ageing. We aimed to determine the cardiac phenotype of the Ercc1 mouse, and how inhibition of activin signalling affects cardiac remodelling using immunological and biochemical analysis. Methods Using immunohistochemical staining, we investigated the cardiac phenotype in 16 week old Ercc1Δ/− progeric and Ercc1+/+ wildtype mice (n=4–6) with or without soluble activin receptor injections from the week 7 (sActRIIB, 10mg/kg). The Ercc1Δ/− mouse displays a deficiency in DNA repair, leading to an accelerated ageing phenotype. Experimentally, injections of the myostatin /activin antagonist called the soluble ActRIIB receptor trap (sActRIIB) can be used to pharmacologically target the activin signalling pathway. Results In Ercc1Δ/− mice at 16 weeks there was a 50% decrease in the heart weight in comparison to Ercc1+/+ wildtype mice (175±13 vs 85±4), (p&lt;0.001). Activin inhibition did not have any effect on the heart weight. To determine the extent of DNA damage, cardiac tissue was stained for γH2Ax. γH2Ax accumulates at double stranded DNA breaks where histone 2A becomes phosphorylated. Ercc1Δ/− mice displayed a 20% increase in double stranded DNA breaks in comparison to the Ercc1+/+ wildtype (0.6±0.5 vs 22.5±2.5 vs 15.8±0.7), (p&lt;0.01). Activin inhibition led to a significant 5% decrease (p&lt;0.05). Oxidative stress was determined by dihydroethidium staining. Ercc1Δ/− mice showed a 30% increase in oxidative stress (33.33±3 vs 49.98±3 vs 36.19±3), (p&lt;0.05). Activin inhibition reversed this increase of oxidative stress in Ercc1Δ/− mice (p&lt;0.05). Finally, cardiac fibrosis was assessed using picrosirius red staining. No differences were observed between the Ercc1Δ/− progerics and Ercc1+/+ wildtype mice, while activin inhibition led to a 50% decrease (4.9±0.3 vs 7.7±1.3 vs 2.9±0.1), (p&lt;0.01). Interestingly, Ercc1Δ/− mice display thicker cardiac interstitial collagen I (1.3±0.01 vs 1.4±0.05 vs 1.3±0.01), (p&lt;0.05). Activin inhibition also reversed this increased interstitial collagen (p&lt;0.05). Conclusion Inhibition of activin receptor signalling brings beneficial effects to the Ercc1Δ/− cardiac phenotype by attenuating oxidative stress, DNA damage and fibrosis. Funding Acknowledgement Type of funding source: None" @default.
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• W3107007605 date "2020-11-01" @default.
• W3107007605 modified "2023-10-01" @default.
• W3107007605 title "Inhibition of the activin receptor improves cardiac remodelling in the ercc1 mouse model of accelerated ageing" @default.
• W3107007605 doi "https://doi.org/10.1093/ehjci/ehaa946.3649" @default.
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