p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities
p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities
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DOI：
10.1073/pnas.1904979116
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发表时间：
2019-09-24
影响因子：
11.1
通讯作者：
Hwang, Paul M.
中科院分区：
文献类型：
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作者：
Li, Jie;Wang, Ping-yuan;Hwang, Paul M.
阿霉素是一种广泛使用的化疗药物，可在部分接受治疗的患者中引起剂量依赖性心脏毒性，但人们对这种易感性的遗传决定因素知之甚少。在这里，我们报告说，p53 的非典型肿瘤抑制活性可以预防临床中分次低剂量阿霉素诱导的小鼠模型中的心脏功能障碍。虽然野生型 (p53(+/+)) 状态相对保留，但缺乏 p53 (p53(-/-)) 的小鼠在多柔比星治疗后出现左心室 (LV) 收缩功能障碍。 p53(-/-) 小鼠的这种功能下降与心脏氧化代谢、线粒体质量和线粒体基因组 DNA (mtDNA) 稳态的下降有关。值得注意的是，p53 R172H（p53（172H/H））纯合敲入突变的小鼠，与p53（-/-）状态一样，缺乏p53的典型肿瘤抑制活性（例如细胞凋亡），但保留了其线粒体生物发生能力，在阿霉素治疗后显示出左心室功能和线粒体的保留。与 p53 缺失状态相反，野生型和突变型 p53 显示出不同的反式激活线粒体转录因子 A (TFAM) 和 p53 诱导核糖核苷酸还原酶 2 (p53R2) 的机制，这些机制参与 mtDNA 转录和维持。重要的是，给小鼠补充 NAD(+) 前体可以防止 mtDNA 耗竭和心脏功能障碍。这些发现表明，mtDNA 的丢失会导致按照模拟临床用药的阿霉素给药方案诱发的心肌病发病机制。鉴于 p53 在阿霉素处理的人诱导多能干细胞 (iPSC) 衍生的心肌细胞中具有类似的 mtDNA 保护作用，因此在血液和骨骼肌细胞中观察到的与心肌病发展相关的线粒体标记物可能具有预后用途。
Doxorubicin is a widely used chemotherapeutic agent that causes dose-dependent cardiotoxicity in a subset of treated patients, but the genetic determinants of this susceptibility are poorly understood. Here, we report that a noncanonical tumor suppressor activity of p53 prevents cardiac dysfunction in a mouse model induced by doxorubicin administered in divided low doses as in the clinics. While relatively preserved in wild-type (p53(+/+)) state, mice deficient in p53 (p53(-/-)) developed left ventricular (LV) systolic dysfunction after doxorubicin treatment. This functional decline in p53(-/-) mice was associated with decreases in cardiac oxidative metabolism, mitochondrial mass, and mitochondrial genomic DNA (mtDNA) homeostasis. Notably, mice with homozygous knockin of the p53 R172H (p53(172H/H)) mutation, which like p53(-/-) state lacks the prototypical tumor suppressor activities of p53 such as apoptosis but retains its mitochondrial biogenesis capacity, showed preservation of LV function and mitochondria after doxorubicin treatment. In contrast to p53-null state, wild-type and mutant p53 displayed distinct mechanisms of transactivating mitochondrial transcription factor A (TFAM) and p53-inducible ribonucleotide reductase 2 (p53R2), which are involved in mtDNA transcription and maintenance. Importantly, supplementing mice with a precursor of NAD(+) prevented the mtDNA depletion and cardiac dysfunction. These findings suggest that loss of mtDNA contributes to cardiomyopathy pathogenesis induced by doxorubicin administered on a schedule simulating that in the clinics. Given a similar mtDNA protection role of p53 in doxorubicin-treated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, the mitochondrial markers associated with cardiomyopathy development observed in blood and skeletal muscle cells may have prognostic utility.