Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Amyloid. 2012 Dec;19(4):191-6. doi: 10.3109/13506129.2012.733741.
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.
免疫球蛋白轻链（AL）型心肌病导致心力衰竭（HF）是系统性淀粉样变性患者发病率和死亡率的重要原因。然而，缺乏稳健的 AL 诱导的心脏功能障碍的体内模型限制了我们探究 AL 心脏疾病机制的能力。为了解决这个问题，我们通过向受精卵注射体外转录的编码淀粉样轻链（aLC）的 mRNA，在斑马鱼胚胎中建立了 AL 型 HF 模型。我们证明，在不显著损害心脏外发育的情况下，aLC 的表达会导致发育中的斑马鱼发生心肌病。表达 aLC 的胚胎的心室表现出收缩功能受损、体积减小和心肌厚度增加，导致充血和水肿，这些特征与淀粉样心肌病的临床表现相似。磷酸化 p38，一种氧化应激的标志物，在响应 aLC 表达时增加。没有发现淀粉样纤维沉积的证据。因此，aLC mRNA 在斑马鱼中的表达会导致心脏毒性作用，而不会导致纤维沉积。这与先前的证据一致，即 aLC 寡聚体在体外介导心脏功能障碍。该模型将允许探索淀粉样病理生理学，并测试减少和逆转淀粉样变性对心肌功能的有害影响的干预措施。
