Berberine inhibits NLRP3 inflammasome activation by upregulating the SIRT6-AMPK pathway to prevent angiotensin II-induced fibrosis and vulnerability to atrial fibrillation.

Abstract

BACKGROUND AND PURPOSE: Our previous clinical study showed that berberine could reduce the occurrence of postoperative atrial fibrillation (AF), but the underlying mechanism remains unknown. Additionally, the effect of SIRT6 in the pathogenesis of AF and whether the anti-arrhythmic effects of berberine are associated with SIRT6 regulation remain uncovered. This study aimed to investigate the role of SIRT6 in the occurrence of AF and the pharmacological effect of berberine on atrial remodeling and AF susceptibility with a focus on SIRT6-AMPK signaling. METHODS: Bioinformatics tools and human atrial sample analysis were conducted to investigate the potential mechanisms. Murine AF model was induced by angiotensin II (Ang II) infusion with or without the treatment of berberine and the adeno-associated virus carrying SIRT6 or SIRT6-specific short hairpin RNA. The protective effect and the underlying mechanisms were examined. RESULTS: NLRP3 inflammasome-mediated inflammatory signaling in atrial tissue was activated, and SIRT6 activity was inhibited in AF patients. Berberine dose-dependently improved atrial structural and electrical remodeling in Ang II-induced mice. Moreover, berberine enhanced atrial antioxidative stress capacity and reduced NLRP3 inflammasome activation. SIRT6 overexpression mimicked these actions. Berberine-mediated SIRT6-AMPK signaling activation was inhibited by SIRT6 knockdown, and berberine-mediated inhibition of NLRP3 inflammasome signaling was compromised. CONCLUSION: These results demonstrate that activation of SIRT6-AMPK signaling protects against Ang II-induced atrial remodeling and AF susceptibility. Berberine prevents Ang II-induced atrial injury by inhibiting NLRP3 inflammasome activation through the SIRT6-AMPK signaling pathway. Its potential as a preventive or therapeutic agent warrants further clinical investigation.