Calpain inhibition protects against atrial fibrillation by mitigating diabetes-associated atrial fibrosis and calcium handling dysfunction in type 2 diabetes mice

Qing Wang; Jinxiang Yuan; Hua Shen; Qi Zhu; Biyi Chen; Jinxi Wang; Weizhong Zhu; Mark A Yorek; Duane D Hall; Zhinong Wang; Long-Sheng Song

doi:10.1016/j.hrthm.2024.02.036

Calpain inhibition protects against atrial fibrillation by mitigating diabetes-associated atrial fibrosis and calcium handling dysfunction in type 2 diabetes mice

Heart Rhythm. 2024 Feb 21:S1547-5271(24)00208-X. doi: 10.1016/j.hrthm.2024.02.036. Online ahead of print.

Authors

Qing Wang¹, Jinxiang Yuan², Hua Shen³, Qi Zhu⁴, Biyi Chen⁵, Jinxi Wang⁵, Weizhong Zhu⁶, Mark A Yorek⁷, Duane D Hall⁵, Zhinong Wang⁸, Long-Sheng Song⁹

Affiliations

¹ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, China; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
² The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, China; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
³ Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Cardiovascular Surgery, Chinese PLA General Hospital, Beijing, China.
⁴ Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
⁵ Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
⁶ Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
⁷ Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Veterans Affairs Iowa City Health Care System, Iowa City, Iowa; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa.
⁸ Department of Cardiothoracic Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China. Electronic address: wangzn007@163.com.
⁹ Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; Department of Veterans Affairs Iowa City Health Care System, Iowa City, Iowa; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa. Electronic address: long-sheng-song@uiowa.edu.

PMID: 38395244
DOI: 10.1016/j.hrthm.2024.02.036

Abstract

Background: 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.

Objective: The purpose of this study was to investigate the role of calpain in diabetes-associated AF, fibrosis, and calcium handling dysfunction.

Methods: DM-associated AF was induced in wild-type (WT) mice and in mice overexpressing the calpain inhibitor calpastatin (CAST-OE) using high-fat diet feeding followed by low-dose streptozotocin injection (75 mg/kg). DM and AF outcomes were assessed by measuring blood glucose levels, fibrosis, and AF susceptibility during transesophageal atrial pacing. Intracellular Ca²⁺ transients, spontaneous Ca²⁺ release events, and intracellular T-tubule membranes were measured by in situ confocal microscopy.

Results: WT mice with DM had significant hyperglycemia, atrial fibrosis, and AF susceptibility with increased atrial myocyte calpain activity and Ca²⁺ 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-induced atrial calpain activity and 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, Ca²⁺ handling, and reduced spontaneous Ca²⁺ release events compared to littermate controls.

Conclusion: This study confirmed that 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 Ca²⁺ homeostasis. Our results support calpain inhibition as a potential therapy for preventing and treating AF in DM patients.

Keywords: Atrial fibrillation; Calcium homeostasis; Calpain; Calpastatin; Diabetes; Fibrosis.

Abstract

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