Chronic and Acute n-3 Polyunsaturated Fatty Acid (n-3 PUFA) Treatments Have Divergent Effects on Cardiac Ion Channel Function

Abstract

Background: Clinical studies suggest that dietary fish oil (FO) supplement (containing n-3 PUFAs) has anti- or pro-arrhythmic effects in different patient populations. The underlying mechanisms are not clear. Objectives: To compare effects of chronic vs acute n-3 PUFA treatment on ion channel function important for shaping cardiac action potential (AP) configuration/duration, and to explore the underlying mechanisms. Methods: Left ventricular myocytes (VMs) from adult rabbits or guinea pigs fed with FO (180 mg/kg n-3 PUFAs) for ≥ 4 weeks or age-matched control are used for patch clamping (AP & ionic current evaluation) and confocal microscopy (protein distribution). Ventricular membrane fractions are used for Western blotting (protein level quantification). Channel-expressing COS-7 cells serve as an in vitro model to test the effects of chronic or acute n-3 PUFA treatment on cardiac channel function/expression. Results: Chronic n-3 PUFA treatment increases ICaL but decreases Ito, IKr and IKs. Correspondingly, AP plateau is elevated and duration is prolonged. Mechanisms for the observed chronic effects include: (a) changes in posttranslational modification involving caveolae-related signaling pathways (no change in Cav1.2 protein level/ distribution but decrease in caveolin-3), and (b) changes in membrane protein trafficking/stability (reduced Kv4.2 protein level). Chronic COS-7 exposure to n-3 PUFA also reduces the protein level of Kv4.2 & KCNQ1, although not Kv1.4, Kv4.3, KChIP2, KCNE1 or hERG. Importantly, acute exposure of VMs to n-3 PUFA reduces ICaL but increases IKs, thus offsetting the chronic effects. Conclusions: FO supplement impacts on cardiac ion channel function by chronic/stable effects, superimposed with acute effects following FO ingestion that can offset the chronic effects but decline with time. Combination of these effects sets up a dynamic pattern of how cardiac electrical activity is influenced by FO supplement.