文献检索，用中文搜 PubMed

Background Sorbin and SH3 domain containing 2 (Sorbs2) protein is a cytoskeletal adaptor with an emerging role in cardiac biology and disease; yet, its potential relevance to adult-onset cardiomyopathies remains underexplored. Sorbs2 global knockout mice display lethal arrhythmogenic cardiomyopathy; however, the causative mechanisms remain unclear. Herein, we examine Sorbs2 dysregulation in heart failure, characterize novel Sorbs2 cardiomyocyte-specific knockout mice (Sorbs2-cKO), and explore associations between Sorbs2 genetic variations and human cardiovascular disease. Methods and Results Bioinformatic analyses show myocardial Sorbs2 mRNA is consistently upregulated in humans with adult-onset cardiomyopathies and in heart failure models. We generated Sorbs2-cKO mice and report that they develop progressive systolic dysfunction and enlarged cardiac chambers, and they die with congestive heart failure at about 1 year old. After 3 months, Sorbs2-cKO mice begin to show atrial enlargement and P-wave anomalies, without dysregulation of action potential-associated ion channel and gap junction protein expressions. After 6 months, Sorbs2-cKO mice exhibit impaired contractility in dobutamine-treated hearts and skinned myofibers, without dysregulation of contractile protein expressions. From our comprehensive survey of potential mechanisms, we found that within 4 months, Sorbs2-cKO hearts have defective microtubule polymerization and compensatory upregulation of structural cytoskeletal and adapter proteins, suggesting that this early intracellular structural remodeling is responsible for contractile dysfunction. Finally, we identified genetic variants that associate with decreased Sorbs2 expression and human cardiac phenotypes, including conduction abnormalities, atrial enlargement, and dilated cardiomyopathy, consistent with Sorbs2-cKO mice phenotypes. Conclusions Our studies show that Sorbs2 is essential for maintaining structural integrity in cardiomyocytes, likely through strengthening the interactions between microtubules and other cytoskeletal proteins at cross-link sites.

背景

Sorbin 和 SH3 结构域包含蛋白 2（Sorbs2）是一种细胞骨架衔接蛋白，在心脏生物学和疾病中具有新兴作用；然而，其与成人发病型心肌病的潜在相关性仍未得到充分探索。Sorbs2 全局敲除小鼠表现出致命性心律失常性心肌病；然而，其致病机制尚不清楚。在此，我们研究了心力衰竭中的 Sorbs2 失调，对 Sorbs2 心肌细胞特异性敲除小鼠（Sorbs2-cKO）进行了特征描述，并探索了 Sorbs2 遗传变异与人类心血管疾病之间的关联。

方法和结果

生物信息学分析显示，心肌 Sorbs2 mRNA 在患有成人发病型心肌病和心力衰竭模型的人类中持续上调。我们生成了 Sorbs2-cKO 小鼠，并报告它们会逐渐出现收缩功能障碍和心脏腔室增大，并在大约 1 岁时因充血性心力衰竭而死亡。3 个月后，Sorbs2-cKO 小鼠开始出现心房扩大和 P 波异常，而动作电位相关离子通道和缝隙连接蛋白表达没有失调。6 个月后，Sorbs2-cKO 小鼠在多巴酚丁胺处理的心脏和去皮肌纤维中表现出收缩功能受损，而收缩蛋白表达没有失调。从我们对潜在机制的全面调查中，我们发现，在 4 个月内，Sorbs2-cKO 心脏的微管聚合出现缺陷，并出现结构性细胞骨架和衔接蛋白的代偿性上调，这表明这种早期的细胞内结构重塑是导致收缩功能障碍的原因。最后，我们确定了与 Sorbs2 表达降低和人类心脏表型相关的遗传变异，包括传导异常、心房扩大和扩张型心肌病，这与 Sorbs2-cKO 小鼠的表型一致。