Cardiomyocyte specific ablation of p53 is not sufficient to block doxorubicin induced cardiac fibrosis and associated cytoskeletal changes.
Cardiomyocyte specific ablation of p53 is not sufficient to block doxorubicin induced cardiac fibrosis and associated cytoskeletal changes.
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DOI：
10.1371/journal.pone.0022801
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Pasumarthi KB
中科院分区：
文献类型：
--
作者：
Feridooni T;Hotchkiss A;Remley-Carr S;Saga Y;Pasumarthi KB
阿霉素(Dox)是一种用于有效治疗几种形式癌症的蒽环类药物。不幸的是，Dox的使用受到限制，因为它与心血管并发症有关，这些并发症表现为急性和慢性心脏毒性。Dox心脏毒性的病理生理机制可能涉及心肌细胞肿瘤抑制蛋白P53的表达增加，进而导致细胞凋亡。目前尚不清楚下调心肌细胞中P53的表达是否会导致心肌纤维化发生率的降低，这是由于心肌细胞丢失而发生的。此外，目前尚不清楚Dox是否会导致心脏血管周围坏死和相关的纤维化。在这项研究中，我们在一个条件基因敲除(CKO)小鼠模型系统中测量了急性Dox治疗对心肌和血管周围细胞凋亡和纤维化的影响，该模型系统在心肌细胞中特异性地含有不活跃的P53等位基因。与携带完整P53等位基因的对照组相比，单剂量Dox(20 mg/kg)处理的CKO小鼠的心肌细胞凋亡率或ROS/RNS水平并未降低。有趣的是，在Dox治疗3天或7天后，CKO小鼠也表现出比对照组更高水平的间质和血管周围纤维化。此外，在cko小鼠中，微管蛋白α-微管蛋白水平的下降并未被阻止，这种下降发生在Dox治疗的反应中。总之，这些结果表明，心肌细胞P53的选择性缺失不足以阻止Dox诱导的心肌ROS/RNS的产生、细胞凋亡、间质纤维化和血管周围纤维化。此外，这些结果支持了P53非依赖的细胞凋亡通路导致Dox诱导的心肌损伤，并强调了血管损伤在Dox诱导的心脏毒性中的重要性。
Doxorubicin (Dox) is an anthracycline used to effectively treat several forms of cancer. Unfortunately, the use of Dox is limited due to its association with cardiovascular complications which are manifested as acute and chronic cardiotoxicity. The pathophysiological mechanism of Dox induced cardiotoxicity appears to involve increased expression of the tumor suppressor protein p53 in cardiomyocytes, followed by cellular apoptosis. It is not known whether downregulation of p53 expression in cardiomyocytes would result in decreased rates of myocardial fibrosis which occurs in response to cardiomyocyte loss. Further, it is not known whether Dox can induce perivascular necrosis and associated fibrosis in the heart. In this study we measured the effects of acute Dox treatment on myocardial and perivascular apoptosis and fibrosis in a conditional knockout (CKO) mouse model system which harbours inactive p53 alleles specifically in cardiomyocytes. CKO mice treated with a single dose of Dox (20 mg/kg), did not display lower levels of myocardial apoptosis or reactive oxygen and nitrogen species (ROS/RNS) compared to control mice with intact p53 alleles. Interestingly, CKO mice also displayed higher levels of interstitial and perivascular fibrosis compared to controls 3 or 7 days after Dox treatment. Additionally, the decrease in levels of the microtubule protein α-tubulin, which occurs in response to Dox treatment, was not prevented in CKO mice. Overall, these results indicate that selective loss of p53 in cardiomyocytes is not sufficient to prevent Dox induced myocardial ROS/RNS generation, apoptosis, interstitial fibrosis and perivascular fibrosis. Further, these results support a role for p53 independent apoptotic pathways leading to Dox induced myocardial damage and highlight the importance of vascular lesions in Dox induced cardiotoxicity.
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