Elevated myocardial SORBS2 and the underlying implications in left ventricular noncompaction cardiomyopathy
| Autor: | Haiwei Du, Jian Huang, Haizhou Pan, Ranxu Zhao, Yingjie Wei, Yanfen Li, Chunyan Li, Shenghua Liu, Fan Liu, Yuanyuan Xie |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
SR Sarcoplasmic reticulum Pathology OCD oriented cell division E-C coupling excitation-contraction coupling Research paper HPLC High-performance liquid chromatography Heart disease SORBS2 HCM hypertrophic cardiomyopathy lcsh:Medicine Muscle Proteins Ryanodine receptor 2 Mice 0302 clinical medicine SORBS2 sorbin and SH3 domain containing 2 Tubulin LVNC left ventricular noncompaction cardiomyopathy Myocytes Cardiac NC normal control Cells Cultured lcsh:R5-920 Isolated Noncompaction of the Ventricular Myocardium Hypertrophic cardiomyopathy RNA-Binding Proteins General Medicine Left ventricular noncompaction cardiomyopathy Junctophilin-2 Up-Regulation hESC CMs Human embryonic stem cell (hESC) derived cardiomyocytes medicine.anatomical_structure JP2 junctophilin 2 030220 oncology & carcinogenesis lcsh:Medicine (General) LVNC AGC Automatic gain control Cardiomyopathy Dilated medicine.medical_specialty Microtubule Heart failure SORBS2-OE Overexpression of the SORBS2 AAV9 Adeno-associated virus ARVC arrhythmogenic right ventricular cardiomyopathy General Biochemistry Genetics and Molecular Biology 03 medical and health sciences RyR2 type two ryanodine receptor Co-IP Co-immunoprecipitation medicine Animals Humans Calcium Signaling LV left ventricular Adaptor Proteins Signal Transducing business.industry lcsh:R Membrane Proteins medicine.disease Embryonic stem cell 030104 developmental biology HEK293 Cells CID Collision-induced dissociation Trabecular meshwork business |
| Zdroj: | EBioMedicine EBioMedicine, Vol 53, Iss, Pp-(2020) |
| ISSN: | 2352-3964 |
| Popis: | 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) Keywords: LVNC, SORBS2, Microtubule, Junctophilin-2, Heart failure |
| Databáze: | OpenAIRE |
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