Atrial Electrical Remodeling in Mice With Cardiac-Specific Overexpression of Angiotensin II Type 1 Receptor

Background Elevated angiotensin II levels are thought to play an important role in atrial electrical and structural remodeling associated with atrial fibrillation. However, the mechanisms by which this remodeling occurs are still unclear. Accordingly, we explored the effects of angiotensin II on atrial remodeling using transgenic mice overexpressing angiotensin II type 1 receptor (AT1R) specifically in cardiomyocytes. Methods and Results Voltage-clamp techniques, surface ECG, programmed electrical stimulations along with quantitative polymerase chain reaction, Western blot, and Picrosirius red staining were used to compare the atrial phenotype of AT1R mice and their controls at 50 days and 6 months. Atrial cell capacitance and fibrosis were increased only in AT1R mice at 6 months, indicating the presence of structural remodeling. Ca2+ (I-CaL) and K+ currents were not altered by AT1R overexpression (AT1R at 50 days). However, I-CaL density and Ca(V)1.2 messenger RNA expression were reduced by structural remodeling (AT1R at 6 months). Conversely, Na+ current (I-Na) was reduced (-65%) by AT1R overexpression (AT1R at 50 days) and the presence of structural remodeling (AT1R at 6 months) yields no further effect. The reduced I-Na density was not explained by lower Na(V)1.5 expression but was rather associated with an increase in sarcolemmal protein kinase C alpha expression in the atria, suggesting that chronic AT1R activation reduced I-Na through protein kinase C alpha activation. Furthermore, connexin 40 expression was reduced in AT1R mice at 50 days and 6 months. These changes were associated with delayed atrial conduction time, as evidenced by prolonged P-wave duration. Conclusions Chronic AT1R activation leads to slower atrial conduction caused by reduced I-Na density and connexin 40 expression.

Automated summary

In this study, chronic AT1R activation was found to result in slower atrial conduction, primarily through reduced I-Na density and decreased connexin 40 expression.