BACKGROUND Left ventricular noncompaction cardiomyopathy (LVNC) is a hereditary heart disease characterized by an excessive trabecular meshwork of deep intertrabecular recesses within the ventricular myocardium. The guidelines for management of LVNC patients aim to improve quality of life by preventing cardiac heart failure. However, the mechanism underlying LVNC-associated heart failure remains poorly understood. METHODS Using protein mass spectrometry analysis, we established that Sorbin And SH3 Domain Containing 2 (SORBS2) is up-regulated in LVNC hearts without changes to structure proteins. We conducted in vivo experiments wherein the heart tissues of wild-type mice were injected with an AAV9 vector to overexpress SORBS2, followed by analysis using echocardiography, T-tubule analysis and Ca2+ imaging to identify functional and morphological changes. In addition, we analyzed the function and structure of SORBS2 overexpressing human embryonic stem cell (hESC) derived cardiomyocytes (hESC-CM) via immunoblotting, immunohistochemistry, immunofluorescence, and confocal Ca2+ imaging. FINDINGS LVNC myocardial tissues feature strongly elevated expression of SORBS2, microtubule densification and redistribution of Junctophilin 2 (JP2). SORBS2 interacts with β-tubulin, promoting its polymerization in 293T cells and hESC-derived CMs. In vivo, cardiac dysfunction, β-tubulin densification, JP2 translocation, T-tubule disorganization and Ca2+ handling dysfunction were observed in mice overexpressing SORBS2. INTERPRETATION We identified a novel mechanism through which SORBS2 interacts with β-tubulin and promotes microtubule densification, eventually effecting JP2 distribution and T-tubule, potentially contributing to heart failure in LVNC disease. FUND: This work was supported by a CAMS Initiative for Innovative Medicine grant (CAMS-I2M, 2016-I2M-1-015 to Y.J.Wei).

中文翻译：

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心肌SORBS2升高及其在左心室非致密性心肌病中的潜在意义。

背景技术左心室非紧致性心肌病（LVNC）是一种遗传性心脏病，其特征在于心室心肌内深小梁间凹的小梁网过多。LVNC患者的治疗指南旨在通过预防心力衰竭来改善生活质量。但是，LVNC相关心力衰竭的机制仍知之甚少。方法使用蛋白质质谱分析法，我们确定LVNC心脏中含Sorbin和SH3结构域的2（SORBS2）被上调，而不改变结构蛋白。我们进行了体内实验，其中向野生型小鼠的心脏组织注射了AAV9载体以过表达SORBS2，然后使用超声心动图进行分析，T管分析和Ca2 +成像可识别功能和形态变化。此外，我们通过免疫印迹，免疫组织化学，免疫荧光和共聚焦Ca2 +成像分析了SORBS2过表达人类胚胎干细胞（hESC）衍生的心肌细胞（hESC-CM）的功能和结构。结论LVNC心肌组织的特征是SORBS2的表达大幅升高，Juncctophilin 2（JP2）的微管致密化和重新分布。SORBS2与β-微管蛋白相互作用，在293T细胞和hESC衍生的CM中促进其聚合。在体内，在过表达SORBS2的小鼠中观察到心脏功能障碍，β-微管蛋白致密化，JP2易位，T管微管紊乱和Ca2 +处理功能障碍。解释我们确定了一种新的机制，SORBS2通过这种机制与β-微管蛋白相互作用并促进微管致密化，最终影响JP2分布和T-管，可能导致LVNC疾病的心力衰竭。资金：这项工作得到了CAMS创新医学计划的资助（CAMS-I2M，2016-I2M-1-015，授予YJWei）。