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Knockout of Sorbin And SH3 Domain Containing 2 (Sorbs2) in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice
Jared M McLendon1,2, Xiaoming Zhang1,2, Daniel S Matasic1,3
1Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA.
Insights
Sorbin and SH3 domain containing 2 (Sorbs2) is crucial for cardiomyocyte structural integrity. Its deficiency causes heart failure in mice and is linked to human cardiovascular diseases.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetics of Heart Disease
Background:
- Sorbin and SH3 domain containing 2 (Sorbs2) is a cytoskeletal adaptor protein with an emerging role in cardiac function.
- Its specific role in adult-onset cardiomyopathies and heart failure mechanisms is largely unexplored.
- Global Sorbs2 knockout mice exhibit lethal arrhythmogenic cardiomyopathy, but the underlying causes are unclear.
Purpose of the Study:
- To investigate Sorbs2 dysregulation in heart failure.
- To characterize Sorbs2 cardiomyocyte-specific knockout (Sorbs2-cKO) mice.
- To explore the association between Sorbs2 genetic variations and human cardiovascular disease.
Main Methods:
- Bioinformatic analysis of myocardial Sorbs2 mRNA levels in human cardiomyopathies and heart failure models.
- Generation and characterization of Sorbs2-cKO mice.
- Assessment of cardiac structure, function, electrophysiology, and intracellular components in Sorbs2-cKO mice.
Main Results:
- Myocardial Sorbs2 mRNA is upregulated in human cardiomyopathies and heart failure.
- Sorbs2-cKO mice develop progressive systolic dysfunction, cardiac chamber enlargement, and congestive heart failure.
- Early defects in microtubule polymerization and cytoskeletal remodeling precede contractile dysfunction in Sorbs2-cKO hearts.
- Genetic variants associated with decreased Sorbs2 expression correlate with human cardiac phenotypes like conduction abnormalities and dilated cardiomyopathy.
Conclusions:
- Sorbs2 is essential for maintaining cardiomyocyte structural integrity, likely by stabilizing microtubule-cytoskeletal protein interactions.
- Sorbs2 deficiency leads to progressive heart failure through intracellular structural remodeling.
- Sorbs2 genetic variations are linked to human cardiovascular diseases, highlighting its clinical relevance.
Abstract:
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.
