Journal article
Calpain inhibition protects against atrial fibrillation by mitigating diabetes-associated atrial fibrosis and calcium handling dysfunction in type 2 diabetes mice
Heart rhythm, Vol.21(7), pp.1143-1151
07/2024
DOI: 10.1016/j.hrthm.2024.02.036
PMID: 38395244
Abstract
Diabetes mellitus (DM) is a major risk factor for atrial structural remodeling and atrial fibrillation (AF). Calpain activity is hypothesized to promote atrial remodeling and AF.
To investigate the role of calpain in diabetes-associated atrial fibrillation, fibrosis, and calcium handling dysfunction.
DM-associated AF was induced in wildtype mice and in mice overexpressing the calpain inhibitor calpastatin (CAST-OE) using high-fat diet (HFD) feeding followed by low dose streptozotocin injection (STZ, 75 mg/kg). DM and AF outcomes were assessed by measuring blood glucose levels, fibrosis, and AF susceptibility during transesophogeal atrial pacing. Intracellular Ca
transients, spontaneous Ca
release events, and intracellular T-tubule membranes were measured by in situ confocal microscopy.
WT mice with DM had significant hyperglycemia, atrial fibrosis, and AF susceptibility with increased atrial myocyte calpain activity and Ca
handling dysfunction relative to control treated animals. CAST-OE mice with DM had a similar level of hyperglycemia as diabetic WT littermates but lacked significant atrial fibrosis and AF susceptibility. DM-induded atrial calpain activity and the downregulation of the calpain substrate junctophilin-2 were prevented by CAST-OE. Atrial myocytes of diabetic CAST-OE mice exhibited improved T-tubule membrane organization, Ca
handling, and reduced spontaneous Ca
release events compared to littermate controls.
We confirm DM promotes calpain activation, atrial fibrosis, and AF in mice. CAST-OE effectively inhibits DM-induced calpain activation and reduces atrial remodeling and AF incidence through improved intracellular Ca
homeostasis. Our results support calpain inhibition as a potential therapy for preventing and treating AF in DM patients.
Details
- Title: Subtitle
- Calpain inhibition protects against atrial fibrillation by mitigating diabetes-associated atrial fibrosis and calcium handling dysfunction in type 2 diabetes mice
- Creators
- Qing Wang - Shanghai Jiao Tong UniversityJinxiang Yuan - Jining Medical UniversityHua Shen - University of IowaQi Zhu - University of IowaBiyi Chen - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAJinxi Wang - University of IowaWeizhong Zhu - Nantong UniversityMark A Yorek - University of IowaDuane D Hall - University of IowaZhinong Wang - Shanghai Changzheng HospitalLong-Sheng Song - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Heart rhythm, Vol.21(7), pp.1143-1151
- DOI
- 10.1016/j.hrthm.2024.02.036
- PMID
- 38395244
- NLM abbreviation
- Heart Rhythm
- eISSN
- 1556-3871
- Grant note
- DOI: 10.13039/100015515, name: The University of Iowa Roy J and Lucille A Carver College of Medicine
- Language
- English
- Electronic publication date
- 02/21/2024
- Date published
- 07/2024
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984560424602771
Metrics
11 Record Views