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

Barbara Szeiffova Bacova,Gerd Wallukat,Vladimir Knezl,Anne Wallukat,Jana Radosinska,Miroslav Barancik,Matus Sykora,Narcis Tribulova,Ludovit Paulis

doi:10.3390/ijms21020526

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-ε signaling; thus, abolish arrhythmia substrate and protect rats with an advanced stage of hypertension from malignant arrhythmias.

Highlights

The global incidence of hypertension is growing that represents a serious health problem if not treated properly
It is important that AA directed against the first or second extracellular loop of the adrenergic β1-receptors (i.e., β1-AR) may play a significant role. β1-adrenoceptor autoantibodies (β1-AA) have been found in patients with dilated cardiomyopathy (DCM) and myocarditis [4,5,6,7,8,9] as well as in dogs suffering from DCM and in hypertensive rats [10,11]. β1-AA can induce agonistic-like effects on spontaneously beating rat cardiomyocytes, i.e., they are able to activate the adenylate cyclase, increase cAMP production, L-type Ca2+ current and action potential duration [10]
We have shown in this study that both male and female rats suffering from an advanced stage of hypertension exhibit a significant increase of circulating β1-AA and incidence of inducible-ventricular fibrillation (VF) compared to non-hypertensive animals

Summary

Introduction

The global incidence of hypertension is growing that represents a serious health problem if not treated properly. Hypertension leads to chronic inflammation, oxidative stress, autoantibodies (AA) production, structural remodeling as well to alterations in intracellular and intercellular signaling. These events promote development of dilated cardiomyopathy (DCM) and subsequent heart failure (HF) as well as cardiac death due to lethal arrhythmias [2,3]. In this context, it is important that AA directed against the first or second extracellular loop of the adrenergic β1-receptors (i.e., β1-AR) may play a significant role. Β1-AA autoimmunity causes idiopathic ventricular arrhythmias in humans [4,6,15] and may contribute to the propensity of hypertensive rat heart to ventricular fibrillation (VF) [2]

Objectives

Methods

Conclusion