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.
Objective: The purpose of this study was to explore the potential role of CD44 and its related signaling in tachypacing-induced downregulation of LTCC.
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-/- 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-/- mice than in wild-type mice. In vivo, burst atrial pacing stimulated less inducibility of AF in CREB inhibitor-treated mice than in controls.
Conclusion: Tachypacing-induced CREB/CD44 signaling contributes to the suppression of LTCC, which provides valuable information about the pathogenesis of atrial modeling and AF.
Keywords: Atrial fibrillation; Atrial remodeling; CD44; Cyclic adenosine monophosphate response element–binding protein; L-type calcium channel.
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