The Role of Tgf-Β/Cd44/Nox Signaling in the Pathogenesis of Atrial Remodeling and Fibrillation

Atrial fibrillation (AF) is a common tachyarrhythmia. Electrical and structural remodeling in atrial myocytes contribute greatly to the pathogenesis of AF. With respect to electrical remodeling in atrial myocytes, accumulating evidence suggests that intracellular Ca2+ overload and handling abnormality constitute the main feature of AF. Elevation of diastolic [Ca2+] through increased sarcoplasmic reticulum (SR) Ca2+ spark frequency is regarded as an important mechanism of AF. Increased Ca2+/calmodulin-dependent protein kinase (CaMK)II-dependent phosphorylation of ryanodine receptor type 2 [RyR2] may lead to increased SR Ca2+ leak, resulting in elevated cytosolic Ca2+ levels. Furthermore, oxidized CaMKII (ox-CaMKII) may be associated with SR Ca2+ leak in atrial myocytes. Therefore, the expression of ox-CaMKII and p-RyR2 and the frequency of Ca2+ spark could be used as important markers of Ca2+ handling abnormality in atrial myocytes. Numerous clinical and experimental studies have demonstrated the association of AF with oxidative stress and NADPH oxidases (NOXs)-derived reactive oxygen species (ROS) production. In this study, we will further clarify the role of NOX and other related signaling in Ca2+ handling abnormality in atrial myocytes. CD44 is a trans-membrane receptor for hyaluronan (HA). HA may mediate signaling interaction between transforming growth factor β (TGF-β) and CD44 in some cells. Our published results show that neutralizing anti-CD44 antibody treatment could diminish pacing-induced AF occurrence in transgenic mice with cardiac over-expression of TGF-β. Furthermore, a recent study in pulmonary fibrosis shows that CD44 is involved in TGF-β/SMAD3-mediated NOX4 induction. In this study, we will explore the interrelation among TGF-β/SMAD3, HA/CD44, and NOX4/ROS signaling in the pathogenesis of atrial remodeling and fibrillation using in vitro, ex vivo, and in vivo models. We will specially focus their roles on Ca2+ handling abnormality in atrial myocytes. Therefore, the aim of our study will investigate: 1. Whether there is an interrelation between TGF-β/SMAD3 and HA/CD44? Does HA/CD44 affect SMAD3 signaling? Could HAS affect TGF-β/SMAD3 signaling? 2. Whether there is an interrelation between HA/CD44 and NOX4? Is it a direct association or indirect? 3. Whether tachypacing-induced Ca2+ handling abnormality is dependent on TGF-β/SMAD3 and HA/CD44 signaling? 4. Whether neutralizing of TGF-β with a monoclonal antibody will alleviate tachypacing-induced Ca2+ handling abnormality and AF occurrence in either ex vivo or in vivo tachypacing model? 5. Whether neutralizing of CD44 with a monoclonal antibody will damper tachypacing-induced Ca2+ handling abnormality and AF occurrence in either ex vivo or in vivo tachypacing model? 6. Whether specific blocking of TGF-β/SMAD3 and HA/CD44 signaling using inhibitors reverses tachypacing-induced Ca2+ handling abnormality and AF occurrence in either ex vivo or in vivo tachypacing model? 7. Whether tachypacing-induced Ca2+ handling abnormality and AF occurrence may decrease in either ex vivo or in vivo tachypacing model of CD44-/- mice? Hopefully, our study will provide a deeper understanding about the interaction among TGF-β/SMAD3, HA/CD44, and NOX4/ROS signaling and their effects on AF. The results of our study may provide a useful target for therapeutic intervention in AF.

Project ID:PC10901-1623
External Project ID:MOST107-2314-B182-072-MY3