Tachycardia-induced CD44/NOX4 signaling is involved in the development of atrial remodeling
Tachycardia-induced CD44/NOX4 signaling is involved in the development of atrial remodeling
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DOI：
10.1016/j.yjmcc.2019.08.006
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发表时间：
2019-10-01
影响因子：
5
通讯作者：
Yeh, Yung-Hsin
中科院分区：
文献类型：
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作者：
Chen, Wei-Jan;Chang, Shang-Hung;Yeh, Yung-Hsin
心房颤动（AF）与心房肌细胞的氧化应激和Ca 2+处理异常有关。我们先前的研究已经证明了透明质酸（HA）的膜受体CD 44参与AF的发病机制。本研究进一步评估了CD 44及其相关信号传导是否介导房性心动过速诱导的氧化应激和Ca 2+处理异常。心房源性心肌细胞（HL-1细胞系）中的心动过速诱导CD 44相关信号传导的激活，包括HA和HA合成酶（HAS）表达。阻断HAS/HA/CD 44信号传导可减弱HL-1心肌细胞中超速起搏诱导的氧化应激（NADPH氧化酶[NOX] 2/4表达）和Ca 2+处理异常（氧化Ca 2 +/钙调蛋白依赖性蛋白激酶II [ox-CaMKII]和磷酸化ryanodine受体2型[p-RyR 2]表达）。此外，CD 44和NOX 4之间的直接关联被记录在快速起搏的HL-1心肌细胞和房颤患者的心房组织中。在体外，从CD 44（-/）-小鼠分离的心房肌细胞中的Ca 2+火花频率低于野生型小鼠。此外，在从野生型小鼠分离的心房肌细胞中施用抗CD 44阻断抗体减少了Ca 2+火花的频率。与野生型小鼠相比，CD 44（-/-）小鼠的体外快速起搏模型显示出较低程度的氧化应激和心房中ox-CaMKII/p-RyR 2的表达。在体内，短阵心房起搏在CD 44（-/-）小鼠中刺激的AF诱导率低于野生型小鼠。总之，心房快速起搏诱导的Ca 2+处理异常是通过CD 44/NOX 4信号转导介导的，这为AF的发展提供了一个可能的解释。
Atrial fibrillation (AF) is associated with oxidative stress and Ca2+-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 Ca2+-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 Ca2+-handling abnormalities (oxidized Ca2+/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, Ca2+ 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 Ca2+ spark. Ex viva 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 Ca2+-handling abnormalities are mediated via CD44/NOX4 signaling, which provides a possible explanation for the development of AF.