Arachidonic acid protects against diabetes-induced atrial fibrillation.

BACKGROUND: Diabetes mellitus (DM) significantly increases the risk of atrial fibrillation (AF), yet the underlying mechanisms remain poorly defined. Arachidonic acid (AA), a key omega-6 fatty acid involved in redox and inflammatory regulation, has been implicated in cardiovascular homeostasis, but its role in diabetes-related atrial remodeling and AF susceptibility is unclear. METHODS: AA levels were measured in atrial tissues and serum from diabetic mice and AF patients. Diabetic mice were supplemented with AA, followed by structural, electrophysiological, and molecular analyses. Transcriptional regulation was assessed using Cut&Tag and dual-luciferase assays. To evaluate the γ-glutamylcysteine synthetase (γ-GCS)/γ-glutamylcysteine (γ-GC) pathway, mice were treated with the γ-GCS inhibitor L-Buthionine- (S, R)-sulfoximine (BSO) or supplemented with γ-GC. RESULTS: AA levels were significantly decreased in diabetic mice and AF patients and negatively correlated with atrial size. AA supplementation reduced atrial remodeling, oxidative stress, inflammation, and AF inducibility in diabetic mice, largely via activation of the Nrf2/γ-GCS pathway. BSO treatment reversed these benefits, while γ-GC supplementation mimicked the effects of AA. CONCLUSION: These results reveal a previously unrecognized protective role of AA against diabetes-induced atrial remodeling and AF, primarily mediated via redox modulation, and suggest AA as a promising therapeutic target in diabetic atrial cardiomyopathy.