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

Autor: Bacova BS; Centre of Experimental Medicine, Institute for Heart Research, SAS, 841 04 Bratislava, Slovakia., Radosinska J; Department of Physiology, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia., Wallukat G; Max-Delbruck Centrum für Molekulare Medizine, 13125 Berlin, Germany.; Berlin Cures GmbH, 10719 Berlin, Germany., Barancik M; Centre of Experimental Medicine, Institute for Heart Research, SAS, 841 04 Bratislava, Slovakia., Wallukat A; Berlin Cures GmbH, 10719 Berlin, Germany., Knezl V; Center of Experimental Medicine SAS, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovakia., Sykora M; Centre of Experimental Medicine, Institute for Heart Research, SAS, 841 04 Bratislava, Slovakia., Paulis L; Institute of Pathophysiology, Faculty of Medicine, Comenius University, 81108 Bratislava, Slovakia., Tribulova N; Centre of Experimental Medicine, Institute for Heart Research, SAS, 841 04 Bratislava, Slovakia.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2020 Jan 14; Vol. 21 (2). Date of Electronic Publication: 2020 Jan 14.
DOI: 10.3390/ijms21020526
Abstrakt: 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 -ε signaling; thus, abolish arrhythmia substrate and protect rats with an advanced stage of hypertension from malignant arrhythmias.
Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Databáze: MEDLINE
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