The Role of Activating Transcription Factor 3 in the Pathogenesis of Atrial Remodeling and Fibrillation in Chronic Kidney Disease

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Patients with chronic kidney disease (CKD) have a high prevalence of AF. There are several electrical and structral remodeling in atrial myocytes contributes greatly to the pathogenesis of AF in CKD patients. The increased expression of ox-CaMKII, p-RyR2, abnormal Ca2+ handling protein homeostasis, and atrial fibrosis plays a vital role in the pathogenesis of AF among CKD patients. Transforming growth factor β (TGF-β) is a major mediator of atrial fibrosis and atrial remodeling in myocytes. Numerous clinical and experimental studies have demonstrated the association of AF with oxidative stress. Of note, previous study indicated that TGF-β was significantly increased in CKD animal model and patients. Activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding (CREB) family of transcription factors, could regulate cellular response to stress including oxidative stress. One recent study indicates that ATF3 regulates canonical TGF-β signaling, especially SMAD3, in systemic sclerosis. Accordingly, in this study, we will follow their findings and plan to elucidate the potential role of ATF3 in the pathogenesis of AF, particularly in atrial electrical and structural remodeling in CKD animal model. In this study, we will investigate the interrelation among TGF-β/SMAD3 and ATF3 in the pathogenesis of atrial electrical/structural remodeling and AF by using in vitro, ex vivo, and in vivo models with CKD. Therefore, the aim of our study will investigate: 1. Whether there is an interrelation between TGF-β1/SMAD3 and ATF3 in atrial myocytes and fibroblasts in CKD model? 2. Whether the suppression of ATF3 will ameliorate the electrical and structural remodeling in atrial cardiomyocytes of CKD model? 3. Whether the suppression of ATF3 will attenuate TGF-β-induced atrial fibrosis in atrial fibroblasts of CKD model? 4. Whether the ATF3 knock-out and CKD mice was associated with a lower risk of AF and remodeling than the control CKD mice ? 5. Whether the up-stream signaling of ATF3 is also involved in the pathogenesis of atrial remodeling and fibrosis in CKD model? Our study may provide a deep insight about the interaction between ATF3 and TGF-β/SMAD3 and their effects on AF pathogenesis in CKD animal model. The results of our study may offer a useful therapeutic target in AF and atrial remodeling in CKD patients.

Project ID:PC10901-1334
External Project ID:MOST108-2314-B182-053-MY2