Abstract
Atrial fibrillation (AF) is the most common arrhythmia in man. Small animal models of AF are rare, limiting the opportunities of mechanistic studies and of evaluating novel treatment strategies. We found that mice can be rendered susceptible to AF by chronic ß-adrenergic stimulation and used this model to test the hypothesis that dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) and endogenously produced cytochrome P450 (CYP)-dependent epoxyeicosanoids protect against AF. Our study included male wild type C57BL/6 mice given either normal chow (WT-n6-group) or a diet supplemented with n-3 PUFAs (2.5% EPA/DHA added to normal chow; WT-n3-group), as well as transgenic littermates with cardiomyocyte-specific overexpression of the human epoxygenase CYP2J2 (CYP-n6 group). All animal groups received 40mg/kg/d of isoproterenol (ISO) or vehicle over 14 days via osmotic mini-pumps. AF induction was tested in vivo by programmed electrical stimulation (PES) and reached 48% (13 of 27 protocols) in ISO-treated WT-n6, compared to 9% (2 of 22) in the vehicle group. ISO-treated WT-n6 mice also featured increased atrial fibrosis, decreased atrial connexin-40 expression, and significantly reduced atrial refractoriness (AERP: 13.1±0.5 vs. 21.7±0.9 ms in vehicle-infused controls). Ventricular refractoriness remained unchanged and ventricular arrhythmias were not inducible. EPA/DHA-supplementation as well as CYP2J2 overexpression significantly reduced ISO-stimulated AF inducibility to 17% (5 of 30 in WT-n3, and 4 of 24 in CYP-n6), decreased atrial fibrosis, and partially prevented connexin-40 down-regulation and AERP reduction (16,1±0,9 in WT-n3 and 17.5±0.5 ms in CYP-n6). Finally, we tested the antiarrhythmic potential of a synthetic analog of 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), an EPA metabolite predominantly produced by CYP2J2 and other epoxygenases. Acute i.v. injection of the 17,18-EEQ compound decreased AF inducibility in ISO-stimulated WT-n6 mice from 67% (14 of 21 in vehicle control) to 33% (10 of 30) and also the mean duration of AF episodes. These results show that ISO-infusion allows establishing a suitable mouse model of AF and indicate an important role of CYP-dependent n-3 PUFA metabolites in preventing AF.
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