Replication Stress Response Modifies Sarcomeric Cardiomyopathy Remodeling.
Replication Stress Response Modifies Sarcomeric Cardiomyopathy Remodeling.
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DOI：
10.1161/jaha.121.021768
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发表时间：
2021-08-03
影响因子：
5.4
通讯作者：
Becker JR
中科院分区：
文献类型：
--
作者：
Pal S;Nixon BR;Glennon MS;Shridhar P;Satterfield SL;Su YR;Becker JR
肌节基因突变导致心肌细胞肥大和病理性心肌重塑。然而，在细胞和器官水平上都存在相当大的表型异质性，表明修饰因子调节这些突变的影响。我们假设肌节功能障碍导致心肌细胞基因毒性应激，这改变了病理性心室重塑。使用肌节蛋白 Mybpc3−/−（心肌肌球蛋白结合蛋白 3）缺陷的小鼠模型，我们发现在心肌病的早期阶段，心肌细胞核 DNA 损伤激增。这伴随着共济失调毛细血管扩张和 rad3 相关磷酸化的选择性增加以及 p53 蛋白积累的增加。 DNA损伤和DNA损伤通路激活的原因是心肌细胞DNA合成失调，导致复制应激。我们发现，选择性抑制共济失调毛细血管扩张和 rad3 相关或 p53 的心肌细胞缺失可减少 Mybpc3−/− 动物的病理性左心室重塑和心肌细胞肥大。携带其他类型肌节基因突变的小鼠和人类也有复制应激反应激活的证据，这与所有研究模型中的心肌细胞非整倍性有关。总的来说，我们的结果表明，肌节突变导致心肌细胞复制应激反应的激活，从而改变肌节心肌病的病理性心肌重塑。
Sarcomere gene mutations lead to cardiomyocyte hypertrophy and pathological myocardial remodeling. However, there is considerable phenotypic heterogeneity at both the cellular and the organ level, suggesting modifiers regulate the effects of these mutations. We hypothesized that sarcomere dysfunction leads to cardiomyocyte genotoxic stress, and this modifies pathological ventricular remodeling. Using a murine model deficient in the sarcomere protein, Mybpc3−/− (cardiac myosin‐binding protein 3), we discovered that there was a surge in cardiomyocyte nuclear DNA damage during the earliest stages of cardiomyopathy. This was accompanied by a selective increase in ataxia telangiectasia and rad3‐related phosphorylation and increased p53 protein accumulation. The cause of the DNA damage and DNA damage pathway activation was dysregulated cardiomyocyte DNA synthesis, leading to replication stress. We discovered that selective inhibition of ataxia telangiectasia and rad3 related or cardiomyocyte deletion of p53 reduced pathological left ventricular remodeling and cardiomyocyte hypertrophy in Mybpc3−/− animals. Mice and humans harboring other types of sarcomere gene mutations also had evidence of activation of the replication stress response, and this was associated with cardiomyocyte aneuploidy in all models studied. Collectively, our results show that sarcomere mutations lead to activation of the cardiomyocyte replication stress response, which modifies pathological myocardial remodeling in sarcomeric cardiomyopathy.