| First Author | Chen WJ | Year | 2019 |
| Journal | J Mol Cell Cardiol | Volume | 135 |
| Pages | 67-78 | PubMed ID | 31419440 |
| Mgi Jnum | J:281558 | Mgi Id | MGI:6376955 |
| Doi | 10.1016/j.yjmcc.2019.08.006 | Citation | Chen WJ, et al. (2019) Tachycardia-induced CD44/NOX4 signaling is involved in the development of atrial remodeling. J Mol Cell Cardiol 135:67-78 |
| abstractText | 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. |
