LSD1 is upregulated in angiotensin II-induced atrial remodeling and regulates oxidative stress, inflammatory signaling, and NLRP3 inflammasome activation associated with atrial fibrillation susceptibility

Lysine-specific demethylase 1 (LSD1) is an epigenetic regulator implicated in cardiovascular disorders; however, its involvement in atrial fibrillation (AF) remains unclear. This study investigated the role of LSD1 in angiotensin II (Ang II)-induced atrial remodeling and AF susceptibility. Male C57BL/6 mice were infused with Ang II (2.0 mg/kg/day) for 28 days to establish an AF-susceptible model. AF inducibility and duration were evaluated using transesophageal burst pacing, and atrial injury and hypertrophy were assessed using biochemical and histological analyses. Ang II infusion significantly increased AF susceptibility and duration, accompanied by atrial hypertrophic remodeling and marked upregulation of LSD1 expression. In vitro, Ang II induced dose-dependent LSD1 expression in HL-1 cardiomyocytes. Silencing LSD1 attenuated Wnt/β-catenin signaling, reduced oxidative stress and inflammatory responses, reduced the expression of hypertrophy-associated markers (ANP and BNP), accompanied by representative morphological changes observed by α-actinin immunofluorescence, and inhibited NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation. Pharmacological activation of Wnt/β-catenin signaling partially reversed these effects. Collectively, these findings identify LSD1 as an upstream epigenetic regulator that promotes Ang II-induced atrial remodeling by independently activating Wnt/β-catenin-dependent hypertrophic signaling and oxidative stress-driven inflammatory pathways, including NLRP3 inflammasome activation, thereby contributing to increased AF susceptibility.