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Tachypacing-induced CREB/CD44 signaling contributes to the suppression of L-type calcium channel expression and the development of atrial remodeling.
- Source :
-
Heart rhythm [Heart Rhythm] 2021 Oct; Vol. 18 (10), pp. 1760-1771. Date of Electronic Publication: 2021 May 20. - Publication Year :
- 2021
-
Abstract
- Background: Atrial fibrillation (AF), a common arrhythmia in clinics, is characterized as downregulation of L-type calcium channel (LTCC) and shortening of atrial action potential duration (APD). Our prior studies have shown the association of CD44 with AF genesis.<br />Objective: The purpose of this study was to explore the potential role of CD44 and its related signaling in tachypacing-induced downregulation of LTCC.<br />Methods and Results: In vitro, tachypacing in atrium-derived myocytes (HL-1 cell line) induced activation (phosphorylation) of cyclic adenosine monophosphate response element-binding protein (CREB). Furthermore, tachypacing promoted an association between CREB and CD44 in HL-1 myocytes, which was documented in atrial tissues from patients with AF. Deletion and mutational analysis of the LTCC promoter along with chromatin immunoprecipitation revealed that cyclic adenosine monophosphate response element is essential for tachypacing-inhibited LTCC transcription. Tachypacing also hindered the binding of p-CREB to the promoter of LTCC. Blockade of CREB/CD44 signaling in HL-1 cells attenuated tachypacing-triggered downregulation of LTCC and shortening of APD. Atrial myocytes isolated from CD44 <superscript>-/-</superscript> mice exhibited higher LTCC current and longer APD than did those from wild-type mice. Ex vivo, tachypacing caused less activation of CREB in CD44 <superscript>-/-</superscript> mice than in wild-type mice. In vivo, burst atrial pacing stimulated less inducibility of AF in CREB inhibitor-treated mice than in controls.<br />Conclusion: Tachypacing-induced CREB/CD44 signaling contributes to the suppression of LTCC, which provides valuable information about the pathogenesis of atrial modeling and AF.<br /> (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Atrial Fibrillation genetics
Atrial Fibrillation metabolism
Blotting, Western
CREB-Binding Protein biosynthesis
Calcium Channels, L-Type biosynthesis
Cell Line
DNA genetics
Disease Models, Animal
Heart Atria metabolism
Heart Atria pathology
Heart Atria physiopathology
Hyaluronan Receptors biosynthesis
Mice
Mice, Inbred C57BL
Myocytes, Cardiac metabolism
Myocytes, Cardiac pathology
Signal Transduction
Atrial Fibrillation therapy
Atrial Remodeling physiology
CREB-Binding Protein genetics
Calcium Channels, L-Type genetics
Cardiac Pacing, Artificial methods
Gene Expression Regulation
Hyaluronan Receptors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1556-3871
- Volume :
- 18
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Heart rhythm
- Publication Type :
- Academic Journal
- Accession number :
- 34023501
- Full Text :
- https://doi.org/10.1016/j.hrthm.2021.05.021