Overexpression of human amyloidogenic light chains causes heart failure in embryonic zebrafish: a preliminary report
Overexpression of human amyloidogenic light chains causes heart failure in embryonic zebrafish: a preliminary report
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DOI：
10.3109/13506129.2012.733741
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发表时间：
2012-12-01
影响因子：
5.5
通讯作者：
Seldin, David C.
中科院分区：
文献类型：
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作者：
Shin, Jordan T.;Ward, Jennifer E.;Seldin, David C.
AL心肌病导致心力衰竭（HF）是系统性淀粉样变性发病率和死亡率的重要原因。然而，缺乏强大的AL诱导的心功能不全的体内模型，限制了我们的能力，以探讨AL心脏病的机制。为了解决这个问题，我们已经开发了一个模型，在斑马鱼胚胎中注射体外转录的编码淀粉样蛋白轻链（aLC）的mRNA到受精卵母细胞的AL HF。我们证明，aLC的表达导致心肌病在发展中的斑马鱼，而不显着损害心外的发展。表达aLC的胚胎的心室表现出收缩力受损、尺寸较小和心肌厚度增加，这导致充血和水肿，这些特征与淀粉样心肌病的临床表现平行。磷酸化p38，氧化应激的标志物，增加aLC的表达。未发现淀粉样纤维沉积的证据。因此，aLC mRNA在斑马鱼中的表达导致心脏毒性作用而没有原纤维沉积。这与表明aLC寡聚体在体外介导心功能障碍的先前证据一致。该模型将允许探索淀粉样蛋白的病理生理学和测试干预措施，以减少和逆转淀粉样变性对心肌功能的有害影响。
AL cardiomyopathy leading to heart failure (HF) represents a significant cause of morbidity and mortality in systemic amyloidosis. However, the paucity of robust in vivo models of AL-induced cardiac dysfunction has limited our ability to probe the mechanisms of AL heart disease. To address this problem, we have developed a model of AL HF in zebrafish embryos by injection of in vitro transcribed mRNA encoding amyloidogenic light chain (aLC) into fertilized oocytes. We demonstrate that expression of aLC causes cardiomyopathy in developing zebrafish without significantly impairing extracardiac development. The cardiac ventricle of embryos expressing aLC exhibit impaired contractility, smaller size, and increased myocardial thickness which result in congestion and edema, features paralleling the clinical manifestations of amyloid cardiomyopathy. Phosphorylated p38, a marker of oxidative stress, was increased in response to aLC expression. No evidence of amyloid fibril deposition was identified. Thus, expression of aLC mRNA in zebrafish results in cardio toxic effects without fibril deposition. This is consistent with prior evidence indicating that aLC oligomers mediate cardiac dysfunction in vitro. This model will allow exploration of amyloid pathophysiology and testing of interventions to reduce and reverse the deleterious effects of amyloidosis on myocardial function.