4-Hydroxychalcone alleviated Angiotensin II-induced atrial fibrillation via immunoproteasome-IKK-NF-κB signaling pathway modulation

Atrial Fibrillation (AF) is the most common type of cardiac arrhythmia and a significant contributor to stroke occurrence. Although 4-Hydroxychalcone (4HCH) has notable anti-inflammatory and antioxidant properties, playing critical therapeutic roles in hypertensive nephropathy and cardiac remodeling, its effects on AF are somewhat unclear, thus forming the basis of this study. Herein, AF was induced in mice via continuous infusion of Angiotensin II (Ang II) at a dose of 2000 ng/kg/min for three weeks. The atrial diameter was assessed through echocardiography, while pathological staining was employed to evaluate atrial inflammation, Oxidative Stress (OS), and fibrosis. Compared to vehicle-treated controls, treatment with 4HCH significantly lowered both the incidence and duration of Ang II-induced AF, while also mitigating atrial dilation, inflammation, OS, and fibrosis. Mechanistically, 4HCH suppressed Ang II-induced immunoproteasome activity, including that of its catalytic subunits (β1i, β2i, and β5i), thus blocking the inflammatory IKKα/β-NF-κB signaling pathway. This inhibition downregulated the TGF-β1/SMAD2/3 pathway and the potassium ion channel protein Kir 2.1, while upregulating connexin 40 (Cx40) and Cx43, thus mitigating atrial fibrosis and fibrillation. Conversely, the Proteasome activator MK-886 increased both immunoproteasome expression and activity, triggering the IKKα/β-NF-κB pathway and leading to atrial inflammation, thus negating 4HCH's protective effects against Ang II-induced atrial remodeling and fibrillation. Overall, 4HCH may confer protective effects against AF, highlighting its potential as a therapeutic candidate for preventing the condition. KEY MESSAGES: 4-Hydroxychalcone (4HCH) confers protection against atrial fibrillation (AF) induced by angiotensin II. 4HCH attenuates the expression and activity of immunosubunits, resulting in the inhibition of IKK-NF-κB signaling and its downstream pathways. Increased activity of the immunoproteasome diminishes the beneficial effects of 4HCH on atrial remodeling and the prevention of AF.

4-Hydroxychalcone; Angiotensin II; Atrial Fibrillation; Fibrosis; Inflammation; Oxidative Stress.