CD44 regulates Epac1-mediated β-adrenergic-receptor-induced Ca2+-handling abnormalities: implication in cardiac arrhythmias

Journal of Biomedical Science

Research

Wei-Jan Chen¹  Yung-Hsin Yeh¹  Shang-Hung Chang¹  Yi-Hsin Chan²  Ying-Ju Lai³  Feng-Chun Tsai⁴  Gwo-Jyh Chang⁵ 

[1]Cardiovascular Division, Chang-Gung Memorial Hospital, 5 Fu-Hsin Street, Guishan, Taoyuan, Taiwan

[2]School of Medicine, College of Medicine, Chang-Gung University, Taoyuan, Taiwan

[3]Cardiovascular Division, Chang-Gung Memorial Hospital, 5 Fu-Hsin Street, Guishan, Taoyuan, Taiwan

[4]School of Medicine, College of Medicine, Chang-Gung University, Taoyuan, Taiwan

[5]School of Traditional Chinese Medicine, College of Medicine, Chang-Gung University, Taoyuan, Taiwan

[6]Department of Respiratory Therapy, College of Medicine, Chang-Gung University, Taoyuan, Taiwan

[7]Division of Cardiovascular Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

[8]Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang-Gung University, Taoyuan, Taiwan

关键词: CD44;    β-Adrenergic receptor;    Exchange proteins directly activated by cAMP;    Osteopontin;    Calcium leak;    Cardiac arrhythmia;   

DOI  :  10.1186/s12929-023-00944-0

 received in 2022-11-02, accepted in 2023-06-26,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundSustained, chronic activation of β-adrenergic receptor (β-AR) signaling leads to cardiac arrhythmias, with exchange proteins directly activated by cAMP (Epac1 and Epac2) as key mediators. This study aimed to evaluate whether CD44, a transmembrane receptor mediating various cellular responses, participates in Epac-dependent arrhythmias.MethodsThe heart tissue from CD44 knockout (CD44−/−) mice, cultured HL-1 myocytes and the tissue of human ventricle were used for western blot, co-immunoprecipitaiton and confocal studies. Line-scanning confocal imaging was used for the study of cellular Ca2+ sparks on myocytes. Optical mapping and intra-cardiac pacing were applied for arrhythmia studies on mice’s hearts.ResultsIn mice, isoproterenol, a β-AR agonist, upregulated CD44 and Epac1 and increased the association between CD44 and Epac1. Isoproterenol upregulated the expression of phospho-CaMKII (p-CaMKII), phospho-ryanodine receptor (p-RyR), and phospho-phospholamban (p-PLN) in mice and cultured myocytes; these effects were attenuated in CD44−/− mice compared with wild-type controls. In vitro, isoproterenol, 8-CPT-cAMP (an Epac agonist), and osteopontin (a ligand of CD44) significantly upregulated the expression of p-CaMKII, p-RyR, and p-PLN; this effect was attenuated by CD44 small interfering RNA (siRNA). In myocytes, resting Ca2+ sparks were induced by isoproterenol and overexpressed CD44, which were prevented by inhibiting CD44. Ex vivo optical mapping and in vivo intra-cardiac pacing studies showed isoproterenol-induced triggered events and arrhythmias in ventricles were prevented in CD44−/− mice. The inducibility of ventricular arrhythmias (VAs) was attenuated in CD44−/− HF mice compared with wild-type HF controls. In patients, CD44 were upregulated, and the association between CD44 and Epac1 were increased in ventricles with reduced contractility.ConclusionCD44 regulates β-AR- and Epac1-mediated Ca2+-handling abnormalities and VAs. Inhibition of CD44 is effective in reducing VAs in HF, which is potentially a novel therapeutic target for preventing the arrhythmias and sudden cardiac death in patients with diseased hearts.

【 授权许可】

CC BY   
© The Author(s) 2023

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