Abstract
Abstract P2010: Cardiomyocyte Knockout Of Sorbs2 Rewires Cytoskeleton And Causes Dilated Cardiomyopathy
Circulation research, Vol.131(Suppl_1), p.AP2010
08/05/2022
DOI: 10.1161/res.131.suppl_1.P2010
Abstract
Sorbs2 is a cardiomyocyte-enriched, cytoskeletal adaptor protein and there is growing interest in understanding its roles in cardiac biology and disease. While Sorbs2 global knockout mice display lethal cardiomyopathy with severe arrhythmias, the underlying mechanisms remain unclear, and if this results from intrinsic loss of Sorbs2 in cardiomyocytes (CM) is unknown, as Sorbs2 is also well-expressed in the nervous system and vasculature. Thus, the potential relevance of Sorbs2 in human cardiomyopathy is underexplored. We aim to characterize the effects and potential mechanisms of CM-specific deletion of Sorbs2 on cardiac structure and function in mice, and to further examine Sorbs2 dysregulation in failing hearts and explore potential links between Sorbs2 genetic variations and human cardiovascular disease phenotypes. We report that heart Sorbs2 expression is consistently upregulated in humans with ischemic and idiopathic cardiomyopathies, and in animal models of heart failure (HF). We generated mice with CM-specific loss of Sorbs2 (Sorbs2-cKO) and found early atrial and ventricular conduction anomalies, despite unaltered expression of primary action potential ion channels and gap junction proteins. At mid-life, Sorbs2-cKO mice exhibit impaired cardiac contractility with cardiomyofibers failing to maintain adequate mechanical tension. These mice develop progressive diastolic and systolic dysfunction, enlarged cardiac chambers, and die with congestive HF at ~1 year of age. Comprehensive survey of potential underlying mechanisms show that Sorbs2-cKO hearts have defective microtubule polymerization and compensatory upregulation of desmin, vinculin, and tubulins. Finally, consistent with our mouse observations, we identified suggestive links between Sorbs2 genetic variants and human cardiac phenotypes, including conduction abnormalities, atrial enlargement, and dilated cardiomyopathy. In conclusion, our studies show that Sorbs2 is essential for maintaining cytoskeletal structural integrity in CM, likely through strengthening the interactions between microtubules and other structural proteins at crosslink sites, and highlights its potential clinical relevance to cardiomyopathy.
Details
- Title: Subtitle
- Abstract P2010: Cardiomyocyte Knockout Of Sorbs2 Rewires Cytoskeleton And Causes Dilated Cardiomyopathy
- Creators
- Jared M McLendon - University of Iowaxiaoming zhang - University of IowaDaniel Matasic - University of IowaMohit Kumar - University of CincinnatiOlha Koval - Iowa City, IAIsabella M Grumbach - CARVER COLLEGE OF MEDICINE, Iowa City, IASakthivel Sadayappan - University of CincinnatiBarry London - University of IowaRyan L Boudreau - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.131(Suppl_1), p.AP2010
- DOI
- 10.1161/res.131.suppl_1.P2010
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 08/05/2022
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Iowa Neuroscience Institute; Radiation Oncology
- Record Identifier
- 9984353647802771
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