Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice
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;...
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| Format: | Article |
| Language: | English |
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Wiley
2022-07-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.122.025687 |
| _version_ | 1811167063310336000 |
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| author | Jared M. McLendon Xiaoming Zhang Daniel S. Matasic Mohit Kumar Olha M. Koval Isabella M. Grumbach Sakthivel Sadayappan Barry London Ryan L. Boudreau |
| author_facet | Jared M. McLendon Xiaoming Zhang Daniel S. Matasic Mohit Kumar Olha M. Koval Isabella M. Grumbach Sakthivel Sadayappan Barry London Ryan L. Boudreau |
| author_sort | Jared M. McLendon |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T16:02:53Z |
| format | Article |
| id | doaj.art-b196424fa3644aaaa2ddb79eeca7f516 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-10T16:02:53Z |
| publishDate | 2022-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-b196424fa3644aaaa2ddb79eeca7f5162023-02-10T09:15:42ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-07-01111310.1161/JAHA.122.025687Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in MiceJared M. McLendon0Xiaoming Zhang1Daniel S. Matasic2Mohit Kumar3Olha M. Koval4Isabella M. Grumbach5Sakthivel Sadayappan6Barry London7Ryan L. Boudreau8Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Pharmacology and Systems Physiology University of Cincinnati OHDepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Pharmacology and Systems Physiology University of Cincinnati OHDepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IABackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.122.025687cardiac arrhythmiacytoskeletal dynamicsgene expression/regulationheart failuremicrotubulesmyocardial contractility |
| spellingShingle | Jared M. McLendon Xiaoming Zhang Daniel S. Matasic Mohit Kumar Olha M. Koval Isabella M. Grumbach Sakthivel Sadayappan Barry London Ryan L. Boudreau Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease cardiac arrhythmia cytoskeletal dynamics gene expression/regulation heart failure microtubules myocardial contractility |
| title | Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice |
| title_full | Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice |
| title_fullStr | Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice |
| title_full_unstemmed | Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice |
| title_short | Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice |
| title_sort | knockout of sorbin and sh3 domain containing 2 sorbs2 in cardiomyocytes leads to dilated cardiomyopathy in mice |
| topic | cardiac arrhythmia cytoskeletal dynamics gene expression/regulation heart failure microtubules myocardial contractility |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.122.025687 |
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