Alamandine Attenuates Hypoxia-Induced Atrial Fibrosis and Atrial Fibrillation by Involving the YAP/TAZ Pathway

Obstructive sleep apnea promotes atrial fibrillation (AF) by activating the renin-angiotensin system (RAS) and increasing angiotensin II. Alamandine(ALA), an angiotensin(1-7)-related peptide with anti-fibrotic properties, has not been thoroughly investigated for its potential effects on atrial fibrosis or its interaction with the YAP/TAZ pathway. This study investigates whether ALA attenuates hypoxia-induced atrial fibrosis and AF, and explores its underlying signaling mechanisms.

Male Sprague-Dawley rats (6-8 weeks old) were divided into four groups: negative control, chronic intermittent hypoxia (CIH), CIH + low-dose ALA (50 µg/kg/day), and CIH + high-dose ALA (250 µg/kg/day). All groups underwent CIH exposure for one month. Subsequently, ALA was administered via subcutaneous osmotic pumps for an additional month, while CIH exposure continued.

Compared with the hypoxia group, ALA treatment led to a significant reduction in the transcription and expression of fibrinogen genes in atrial tissue, a decrease in left atrial area, and less atrial fibrosis-effects that were more pronounced with higher doses. ALA administration also markedly decreased the incidence and duration of AF, reduced atrial conduction heterogeneity, and increased conduction velocity. Furthermore, ALA treatment attenuated the hypoxia-induced upregulation of YAP/TAZ protein expression and nuclear translocation, as well as the elevation in plasma angiotensin II levels.

ALA treatment attenuated chronic intermittent hypoxia-induced atrial fibrosis and reduced AF susceptibility with more pronounced effects observed at higher doses. These results highlight the potential translational value of ALA treatment in reducing AF-related morbidity, possibly via modulation of the YAP/TAZ pathway.