Institute of Cardiovascular and Metabolic Research, School of Biological Sciences, Health and Life Sciences Building, University of Reading, Whiteknights, Reading RG6 6UB, UK.
Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Commonwealth Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Dis Model Mech. 2022 May 1;15(5). doi: 10.1242/dmm.049424. Epub 2022 May 9.
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.
在心脏中，衰老与 DNA 损伤、氧化应激、纤维化和激活素信号通路的激活有关，导致心脏功能障碍。目前尚不清楚激活素信号通路阻断对早衰症的心脏影响。本研究通过减弱 DNA 切除和修复所需的 Ercc1 水平来研究早衰症引起的心脏效应，以及使用可溶性激活素受体 IIB（sActRIIB）阻断激活素信号的影响。Ercc1Δ/- 心脏中的 DNA 损伤和氧化应激显著增加，但 sActRIIB 治疗可降低其损伤。sActRIIB 治疗可改善 Ercc1Δ/- 心脏的心脏收缩功能并诱导心肌细胞肥大。RNA 测序分析显示，在 Ercc1Δ/- 心脏中，促氧化剂表达增加，抗氧化剂基因表达减少，而 sActRIIB 治疗可逆转这种效应。Ercc1Δ/- 心脏还表达更高水平的抗肥厚基因和降低的促肥厚基因水平，sActRIIB 治疗也可逆转这种效应。这些结果首次表明，抑制激活素 A 受体信号通路可减轻 Ercc1 缺陷小鼠的心脏功能障碍、病理性组织重塑和基因表达，并为心脏疾病提供了一个潜在的新治疗靶点。
