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Suppression of β1-adrenoceptor autoantibodies is involved in the antiarrhythmic effects of omega-3 fatty acids in male and female hypertensive rats

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Item Type:Article
Title:Suppression of β1-adrenoceptor autoantibodies is involved in the antiarrhythmic effects of omega-3 fatty acids in male and female hypertensive rats
Creators Name:Bacova, B.S. and Radosinska, J. and Wallukat, G. and Barancik, M. and Wallukat, A. and Knezl, V. and Sykora, M. and Paulis, L. and Tribulova, N.
Abstract:The arrhythmogenic potential of β1-adrenoceptor autoantibodies (β1-AA), as well as antiarrhythmic properties of omega-3 in heart diseases, have been reported while underlying mechanisms are poorly understood. We aimed to test our hypothesis that omega-3 (eicosapentaenoic acid-EPA, docosahexaenoic acid-DHA) may inhibit matrix metalloproteinase (MMP-2) activity to prevent cleavage of β1-AR and formation of β1-AA resulting in attenuation of pro-arrhythmic connexin-43 (Cx43) and protein kinase C (PKC) signaling in the diseased heart. We have demonstrated that the appearance and increase of β1-AA in blood serum of male and female 12-month-old spontaneously hypertensive rats (SHR) was associated with an increase of inducible ventricular fibrillation (VF) comparing to normotensive controls. In contrast, supplementation of hypertensive rats with omega-3 for two months suppressed β1-AA levels and reduced incidence of VF. Suppression of β1-AA was accompanied by a decrease of elevated myocardial MMP-2 activity, preservation of cardiac cell membrane integrity and Cx43 topology. Moreover, omega-3 abrogated decline in expression of total Cx43 as well as its phosphorylated forms at serine 368 along with PKC-ε, while decreased pro-fibrotic PKC-δ levels in hypertensive rat heart regardless the sex. The implication of MMP-2 in the action of omega-3 was also demonstrated in cultured cardiomyocytes in which desensitization of β1-AR due to permanent activation of β1-AR with isoproterenol was prevented by MMP-2 inhibitor or EPA. Collectively, these data support the notion that omega-3 via suppression of β1-AA mechanistically controlled by MMP-2 may attenuate abnormal of Cx43 and PKC signaling; thus, abolish arrhythmia substrate and protect rats with an advanced stage of hypertension from malignant arrhythmias.
Keywords:Essential Hypertension, Autoantibody, Lethal Arrhythmias, Connexin-43, Omega-3, Animals, Rats
Source:International Journal of Molecular Sciences
Page Range:526
Date:14 January 2020
Official Publication:https://doi.org/10.3390/ijms21020526
PubMed:View item in PubMed

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