Galectin‐3 enhances atrial remodelling and arrhythmogenesis through CD98 signalling

• Published in: Acta Physiologica 2022-03, Vol.234 (3), p.e13784-n/a
• Main Authors: Cheng, Wan‐Li, Chen, Yao‐Chang, Li, Shao‐Jung, Lee, Ting‐I, Lee, Ting‐Wei, Higa, Satoshi, Chung, Cheng‐Chih, Kao, Yu‐Hsun, Chen, Shih‐Ann, Chen, Yi‐Jen
• Format: Article
• Language: English
• Subjects: Action potential; Adenosine triphosphatase; Animals; Antibodies; atrial ectopy; Atrial Fibrillation - metabolism; Atrial Fibrillation - pathology; Atrial Remodeling; Ca2+/calmodulin-dependent protein kinase II; Calcium (reticular); Calcium - metabolism; Calcium homeostasis; Calcium Signaling; Calcium signalling; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calmodulin; CaMKII; Cardiomyocytes; CD98; Fibrillation; Fibrosis; Galectin 3 - metabolism; galectin‐3; Homeostasis; Humans; Immunohistochemistry; Kinases; Mice; Myocytes; Myocytes, Cardiac - metabolism; Na+/Ca2+ exchanger; NF-kappa B - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Phosphorylation; Potassium; Potassium - metabolism; Pyrin protein; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; RyR2; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - metabolism; Signal transduction; Sodium channels (voltage-gated); Sodium-Calcium Exchanger - metabolism; Telemetry; Western blotting
• ISSN: 1748-1708; 1748-1716
• DOI: 10.1111/apha.13784

Aim Galectin‐3 (Gal‐3) is a biomarker of atrial fibrillation (AF) that mediates atrial inflammation. CD98 is the membrane surface receptor for Gal‐3. Nevertheless, the role of the Gal‐3/CD98 axis in atrial arrhythmogenesis is unclear. In this study, we investigated the effects of Gal‐3/CD98 signalling on atrial pathogenesis. Methods Whole cell patch clamp and western blotting were used to analyse calcium/potassium homeostasis and calcium‐related signalling in Gal‐3‐administrated HL‐1 atrial cardiomyocytes with/without CD98 neutralized antibodies. Telemetry electrocardiographic recording, Masson's trichrome staining and immunohistochemistry staining of atrium were obtained from mice having received tail‐vein injections with Gal‐3. Results Gal‐3‐treated HL‐1 myocytes had a shorter action potential duration, smaller L‐type calcium current, increased sarcoplasmic reticulum (SR) calcium content, Na+/Ca2+ exchanger (NCX) current, transient outward potassium current, and ultrarapid delayed rectifier potassium current than control cells had. Gal‐3‐treated HL‐1 myocytes had greater levels of SR Ca2+ATPase, NCX, Nav1.5, and NLR family pyrin domain containing 3 (NLRP3) expression and increased calcium/calmodulin‐dependent protein kinase II (CaMKII), ryanodine receptor 2 (RyR2), and nuclear factor kappa B (NF‐κB) phosphorylation than control cells had. Gal‐3‐mediated activation of CaMKII/RyR2 pathway was diminished in the cotreatment of anti‐CD98 antibodies. Mice that were injected with Gal‐3 had more atrial ectopic beats, increased atrial fibrosis, and activated NF‐κB/NLRP3 signalling than did control mice (nonspecific immunoglobulin) or mice treated with Gal‐3 and anti‐CD98 antibodies. Conclusion Gal‐3 recombinant protein administration increases atrial fibrosis and arrhythmogenesis through CD98 signalling. Targeting Gal‐3/CD98 axis might be a novel therapeutic strategy for patients with AF and high Gal‐3 levels.