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Open AccessArticle

Suppression of β1-Adrenoceptor Autoantibodies is Involved in the Antiarrhythmic Effects of Omega-3 Fatty Acids in Male and Female Hypertensive Rats

1
Centre of Experimental Medicine, Institute for Heart Research, SAS, 841 04 Bratislava, Slovakia
2
Department of Physiology, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
3
Max-Delbruck Centrum für Molekulare Medizine, 13125 Berlin, Germany
4
Berlin Cures GmbH, 10719 Berlin, Germany
5
Center of Experimental Medicine SAS, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovakia
6
Institute of Pathophysiology, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(2), 526; https://doi.org/10.3390/ijms21020526
Received: 17 December 2019 / Revised: 9 January 2020 / Accepted: 10 January 2020 / Published: 14 January 2020
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. View Full-Text
Keywords: rats; essential hypertension; autoantibody; lethal arrhythmias; connexin-43; omega-3 rats; essential hypertension; autoantibody; lethal arrhythmias; connexin-43; omega-3
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Szeiffova Bacova, B.; Radosinska, J.; Wallukat, G.; Barancik, M.; Wallukat, A.; Knezl, V.; Sykora, M.; Paulis, L.; Tribulova, N. Suppression of β1-Adrenoceptor Autoantibodies is Involved in the Antiarrhythmic Effects of Omega-3 Fatty Acids in Male and Female Hypertensive Rats. Int. J. Mol. Sci. 2020, 21, 526.

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