Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L-type calcium channel

Autophagy, a bidirectional degradative process extensively occurring in eukaryotes, has been revealed as a potential therapeutic target for several cardiovascular diseases. However, its role in atrial fibrillation (AF) remains largely unknown. This study aimed to determine the role of autophagy in atrial electrical remodeling under AF condition. Here, we reported that autophagic flux was markedly activated in atria of persistent AF patients and rabbit model of atrial rapid pacing (RAP). We also observed that the key autophagy-related gene7 (ATG7) significantly upregulated in AF patients as well as tachypacing rabbits. Moreover, lentivirus-mediated ATG7 knockdown and overexpression in rabbits were employed to clarify the effects of autophagy on atrial electrophysiology via intracardiac operation and patch-clamp experiments. Lentivirus-mediated ATG7 knockdown or autophagy inhibitor chloroquine (CQ) restored the shortened atrial effective refractory period (AERP) and alleviated the AF vulnerability caused by tachypacing in rabbits. Conversely, ATG7 overexpression significantly promoted the incidence and persistence of AF and decreased L-type calcium channel (Cav1.2 α-subunits), along with abbreviated action potential duration (APD) and diminished L-type calcium current (I(Ca,L)). Furthermore, the co-localization and interaction of Cav1.2 with LC3B-positive autophagosomes enhanced when autophagy was activated in atrial myocytes. Tachypacing-induced autophagic degradation of Cav1.2 required ubiquitin signal through the recruitment of ubiquitin-binding proteins RFP2 and p62, which guided Cav1.2 to autophagosomes. These findings suggest that autophagy induces atrial electrical remodeling via ubiquitin-dependent selective degradation of Cav1.2 and provide a novel and promising strategy for preventing AF development.