Tachycardia-induced CD44/NOX4 signaling is involved in the development of atrial remodeling. (October 2019)

• Record Type: Journal Article
• Authors: Chen, Wei-Jan; Chang, Shang-Hung; Chan, Yi-Hsin; Lee, Jia-Lin; Lai, Ying-Ju; Chang, Gwo-Jyh; Tsai, Feng-Chun; Yeh, Yung-Hsin
• Is Part Of: Journal of molecular and cellular cardiology. Volume 135(2019)
• Page Start: 67
• Page End: 78
• Publication Date: 2019-10
• Subjects: Atrial fibrillation -- Ca2+/calmodulin-dependent protein kinase -- CD44 -- Hyaluronan -- NADPH oxidase; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2019.08.006
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: 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. Highlights: Tachypacing induces an activation of HAS/HA/CD44 signaling in atrial myocytes. There is a direct association between CD44 and NOX4 in tachy-paced atrial myocytes. Blockade of CD44 signaling attenuates tachypacing-induced oxidative stress, Ca 2+ -handling abnormalities, and atrial fibrillation. Atrial tachypacing-induced Ca 2+ -handling abnormalities are mediated via CD44/NOX4 signaling.