心肌细胞中DNA修复机制的丧失会诱导扩张的心肌病
Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy
影响因子:7.10000
分区:医学1区 Top / 老年医学1区 细胞生物学2区
发表日期:2023 Apr
作者:
Chathurika Henpita, Rajesh Vyas, Chastity L Healy, Tra L Kieu, Aditi U Gurkar, Matthew J Yousefzadeh, Yuxiang Cui, Aiping Lu, Luise A Angelini, Ryan D O'Kelly, Sara J McGowan, Sanjay Chandrasekhar, Rebecca R Vanderpool, Danielle Hennessy-Wack, Mark A Ross, Timothy N Bachman, Charles McTiernan, Smitha P S Pillai, Warren Ladiges, Mitra Lavasani, Johnny Huard, Donna Beer-Stolz, Claudette M St Croix, Simon C Watkins, Paul D Robbins, Ana L Mora, Eric E Kelley, Yinsheng Wang, Timothy D O'Connell, Laura J Niedernhofer
摘要
心肌病是心肌的进行性疾病，导致收缩性受损。已知遗传毒性癌症疗法是心肌病的有效驱动因素，而自发疾病的原因尚不清楚。为了检验内源性遗传毒性胁迫有助于心肌病的假设，我们使用ERCC1的flox erlox等位基因和在肌肉特异性的肌酸肌酐激酶（CKMM）启动子（CKMM）启动子或eRCCC1-Ercc1-/eccc1-recc1-ercc1-ercc1）中（ERCC1-）中（ERCC1-）中（ERCC1-滴定者）（ERCC1-）中（Ercc1-）删除了DNA修复基因ERCC1。 CKMM-CRE / - ; ERCC1- /FL小鼠突然出现了7个月大的心脏病。作为年轻人，ckmm-cre / - ; ercc1- /fl小鼠的心脏在结构和功能上是正常的，但是到6个月的年龄，有明显的心室扩张，壁稀疏，间质纤维化和收缩功能障碍，指示了扩张性心肌疗法。来自组织特异性或全身模型的心脏组织表现出凋亡的凋亡增加和CKMM-CRE / - ; ERCC1- /FL小鼠的心肌细胞增加，对基因毒素过敏，导致细胞凋亡。 p53水平和靶基因表达，包括几种抗氧化剂，在CKMM-CRE/ - ; ERCC1-/FL和ERCC1-/D小鼠中增加了心脏组织中。尽管如此，来自老年突变小鼠的心脏组织显示出氧化应激增加的证据。 p53的遗传或药理抑制减弱了凋亡和改善的疾病标志物。同样，线粒体靶向过氧化氢酶的过表达改善了疾病标记。这些数据共同支持以下结论：内源性内源性的DNA损伤可以驱动心脏病，并通过p53的长期激活和增加氧化应激，驱动心肌细胞凋亡，扩张心肌病和猝死来机械地进行。
Abstract
Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1-/D mice). Ckmm-Cre+/- ;Ercc1-/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre+/- ;Ercc1-/fl mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre+/- ;Ercc1-/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre+/- ;Ercc1-/fl and Ercc1-/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.