Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish
Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish
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DOI：
10.1152/ajpheart.00186.2013
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发表时间：
2013-07-01
影响因子：
4.8
通讯作者：
Liao, Ronglih
中科院分区：
文献类型：
--
作者：
Mishra, Shikha;Guan, Jian;Liao, Ronglih
系统性淀粉样轻链（AL）淀粉样变性与由循环AL轻链（AL-LC）蛋白的直接心脏毒性作用和AL原纤维组织浸润的间接作用引起的快速进行性和致死性心肌病相关。心脏淀粉样变性对标准心力衰竭疗法具有耐药性，迄今为止，这些患者的治疗选择有限。心脏淀粉样变性和AL-LC心脏毒性发展的潜在机制在很大程度上是未知的，它们的研究受到缺乏合适的体内模型系统的限制。在这里，我们建立了人AL-LC诱导的心脏毒性的体内斑马鱼模型。从AL心肌病患者分离的AL-LC或从多发性骨髓瘤患者分离的对照非淀粉样蛋白生成LC蛋白（Con-LC）在受精后48 h直接注射到斑马鱼的循环中。相对于Con-LC，AL-LC注射导致心脏功能受损、心包水肿和细胞死亡增加，最终导致存活率受损，2周内死亡率为100%，与AL原纤维沉积无关。先前的研究表明，AL-LC诱导的心脏毒性的发病机制中存在非经典的p38 MAPK激活，通过SB-203580抑制p38 MAPK可挽救AL-LC诱导的斑马鱼心脏功能障碍和细胞死亡，并降低死亡率。这种AL-LC心脏毒性的体内斑马鱼模型表明，AL-LC心脏毒性信号传导反应中p38 MAPK的拮抗作用可能有助于改善AL心肌病的心脏功能和死亡率。此外，这种体内模型系统将允许进一步研究AL心脏毒性的分子基础和鉴定新的治疗策略。
Systemic amyloid light-chain (AL) amyloidosis is associated with rapidly progressive and fatal cardiomyopathy resulting from the direct cardiotoxic effects of circulating AL light chain (AL-LC) proteins and the indirect effects of AL fibril tissue infiltration. Cardiac amyloidosis is resistant to standard heart failure therapies, and, to date, there are limited treatment options for these patients. The mechanisms underlying the development of cardiac amyloidosis and AL-LC cardiotoxicity are largely unknown, and their study has been limited by the lack of a suitable in vivo model system. Here, we establish an in vivo zebrafish model of human AL-LC-induced cardiotoxicity. AL-LC isolated from AL cardiomyopathy patients or control nonamyloidogenic LC protein isolated from multiple myeloma patients (Con-LC) was directly injected into the circulation of zebrafish at 48 h postfertilization. AL-LC injection resulted in impaired cardiac function, pericardial edema, and increased cell death relative to Con-LC, culminating in compromised survival with 100% mortality within 2 wk, independent of AL fibril deposition. Prior work has implicated noncanonical p38 MAPK activation in the pathogenesis of AL-LC-induced cardiotoxicity, and p38 MAPK inhibition via SB-203580 rescued AL-LC-induced cardiac dysfunction and cell death and attenuated mortality in zebrafish. This in vivo zebrafish model of AL-LC cardiotoxicity demonstrates that antagonism of p38 MAPK within the AL-LC cardiotoxic signaling response may serve to improve cardiac function and mortality in AL cardiomyopathy. Furthermore, this in vivo model system will allow for further study of the molecular underpinnings of AL cardiotoxicity and identification of novel therapeutic strategies.