Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice.
Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice.
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DOI：
10.1161/jaha.122.025687
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发表时间：
2022-07-05
影响因子：
5.4
通讯作者：
Boudreau, Ryan L.
中科院分区：
文献类型：
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作者：
McLendon, Jared M.;Zhang, Xiaoming;Matasic, Daniel S.;Kumar, Mohit;Koval, Olha M.;Grumbach, Isabella M.;Sadayappan, Sakthivel;London, Barry;Boudreau, Ryan L.
关键词：
含有 Sorbin 和 SH3 结构域 2 (Sorbs2) 蛋白是一种细胞骨架接头蛋白，在心脏生物学和疾病中发挥着新兴作用；然而，其与成人发病的心肌病的潜在相关性仍未得到充分探索。 Sorbs2全基因敲除小鼠表现出致死性心律失常性心肌病；然而，其致病机制仍不清楚。在此，我们检查了心力衰竭中的 Sorbs2 失调，表征了新型 Sorbs2 心肌细胞特异性敲除小鼠 (Sorbs2-cKO)，并探讨了 Sorbs2 遗传变异与人类心血管疾病之间的关联。生物信息分析显示，在患有成人心肌病的人和心力衰竭模型中，心肌 Sorbs2 mRNA 持续上调。我们培育了 Sorbs2-cKO 小鼠，并报告它们出现进行性收缩功能障碍和心室扩大，并在大约 1 岁时死于充血性心力衰竭。 3个月后，Sorbs2-cKO小鼠开始表现出心房扩大和P波异常，但动作电位相关离子通道和间隙连接蛋白表达没有失调。 6 个月后，Sorbs2-cKO 小鼠经多巴酚丁胺处理的心脏和带皮肌纤维表现出收缩性受损，但收缩蛋白表达没有失调。通过对潜在机制的全面调查，我们发现在 4 个月内，Sorbs2-cKO 心脏存在微管聚合缺陷以及结构细胞骨架和接头蛋白的代偿性上调，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，我们发现了与 Sorbs2 表达减少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，与 Sorbs2-cKO 小鼠表型一致。我们的研究表明，Sorbs2 对于维持心肌细胞的结构完整性至关重要，可能是通过加强微管与其他细胞骨架蛋白在交联位点之间的相互作用来实现的。
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. 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. 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.
DOI：
10.1083/jcb.200308055
发表时间：
2004-05-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Miller AL;Wang Y;Mooseker MS;Koleske AJ
通讯作者：
Koleske AJ