Tachycardia-induced CD44/NOX4 signaling is involved in the development of atrial remodeling.

Autor: Chen WJ; Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: wjchen@adm.cgmh.org.tw., Chang SH; Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan., Chan YH; Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan., Lee JL; Institute of Molecular and Cellular Biology and Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan., Lai YJ; Department of Respiratory Therapy, Chang Gung University College of Medicine, Tao-Yuan, Taiwan., Chang GJ; Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Tao-Yuan, Taiwan., Tsai FC; Division of Cardiac Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan., Yeh YH; Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: yeongshinn@cgmh.org.tw.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2019 Oct; Vol. 135, pp. 67-78. Date of Electronic Publication: 2019 Aug 13.
DOI: 10.1016/j.yjmcc.2019.08.006
Abstrakt: Atrial fibrillation (AF) is associated with oxidative stress and Ca 2+ -handling abnormalities in atrial myocytes. Our prior study has demonstrated the involvement of CD44, a membrane receptor for hyaluronan (HA), in the pathogenesis of AF. This study further evaluated whether CD44 and its related signaling mediate atrial tachycardia-induced oxidative stress and Ca 2+ -handling abnormalities. Tachypacing in atrium-derived myocytes (HL-1 cell line) induced the activation of CD44-related signaling, including HA and HA synthase (HAS) expression. Blocking HAS/HA/CD44 signaling attenuated tachypacing-induced oxidative stress (NADPH oxidase [NOX] 2/4 expression) and Ca 2+ -handling abnormalities (oxidized Ca 2+ /calmodulin-dependent protein kinase II [ox-CaMKII] and phospho-ryanodine receptor type 2 [p-RyR2] expression) in HL-1 myocytes. Furthermore, a direct association between CD44 and NOX4 was documented in tachy-paced HL-1 myocytes and atrial tissues from AF patients. In vitro, Ca 2+ spark frequencies in atrial myocytes isolated from CD44 -/- mice were lower than those from wild-type mice. Furthermore, administration of an anti-CD44 blocking antibody in atrial myocytes isolated from wild-type mice diminished the frequency of Ca 2+ spark. Ex vivo tachypacing models of CD44 -/- mice exhibited a lower degree of oxidative stress and expression of ox-CaMKII/p-RyR2 in their atria than those of wild-type mice. In vivo, burst atrial pacing stimulated a less inducibility of AF in CD44 -/- mice than in wild-type mice. In conclusion, atrial tachypacing-induced Ca 2+ -handling abnormalities are mediated via CD44/NOX4 signaling, which provides a possible explanation for the development of AF.
(Copyright © 2019. Published by Elsevier Ltd.)
Databáze: MEDLINE
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