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Hypertension-induced myocardial remodeling is known to be associated with increased propensity to malignant arrhythmias and sudden death partially due to alterations in cell-to-cell coupling protein, connexin-43 (Cx43) at the gap junctions. We investigated whether omega-3 fatty acids diet can protect from malignant arrhythmias via modulation of intercellular Cx43-mediated signaling and intracellular signaling mediated by protein kinase C (PKC) at early and late stage of structural remodeling.Untreated male 3 and 12-month-old spontaneously hypertensive rats (SHR) and age-matched healthy Wistar rats were compared with animals supplemented by omega-3 FA (EPA + DHA 30 mg/day) for two month. Body weight, blood pressure, glucose and plasma lipids profile were monitored. Left ventricular tissues were taken for immunoblotting of Cx43 and PKC-isoforms. In situ immunostaining of Cx43 and electron microscopy were performed to examine distribution and subcellular alterations of gap junctions. Langendorff-heart preparation was used to test VF inducibility.Immunobloting of all rat hearts revealed conventional patterns of Cx43 expression, i.e. two phosphorylated forms Cx43 (P-Cx43) that are needed for the function of Cx43 channels and one non-phosphorylated (noP-Cx43) form. Neither total Cx43 expression nor P-Cx43 was significantly altered in young unlike old SHR heart, which exhibited marked decrease of both parameters. However, the ratio of P-Cx43 to total Cx43 was reduced (P < 0.05) in young SHR hearts while markedly increased due to omega-3 FA diet. Moreover, omega-3 FA enhanced significantly both P-Cx43 and total Cx43 levels in old SHR. In addition, abnormal distribution (lateralization and inernalization) of Cx43-positive gap junctions was attenuated by athe treatment. Expression of PKC-epsilon, which phosphorylates Cx43, was significantly decreased in both young and old SHR, while augmented due to omega-3 FA diet. On the other hand, the expression of PKC-delta (which promotes fibrosis) was increased in the hearts of SHR and suppressed by the treatment. Furthermore, omega-3 FA diet significantly reduced incidence of electrically-inducible VF in both young and old SHR.Results indicate that both young and old hypertensive rats benefit from omega-3 fatty acids diet due to alleviation of myocardial abnormalities in connexin-43 and protein kinase-C signaling that was associated with suppression of malignant arrhythmias.This work was supported by VEGA 2/0046/12 grant.