Influence of Mechanical Circulatory Support on Endothelin Receptor Expression in Human Left Ventricular Myocardium from Patients with Dilated Cardiomyopathy (DCM).

Florian Gärtner,Daniela Baurichter,Getu Abraham,Hendrik Milting,Astrid Kassner

doi:10.1371/journal.pone.0169896

Florian Gärtner, Daniela Baurichter + Show 3 more

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https://doi.org/10.1371/journal.pone.0169896

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Abstract

BackgroundIn terminal failing hearts ventricular assist devices (VAD) are implanted as a bridge to transplantation. Endothelin receptor (ETR) antagonists are used for treatment of secondary pulmonary hypertension in VAD patients. However, the cardiac ETR regulation in human heart failure and during VAD support is incompletely understood.MethodsIn paired left ventricular samples of 12 dilated cardiomyopathy patients we investigated the density of endothelin A (ETA) and B (ETB) receptors before VAD implantation and after device removal. Left ventricular samples of 12 non-failing donor hearts served as control. Receptor quantification was performed by binding of [125I]-ET-1 in the presence of nonselective and ETA selective ETR ligands as competitors. Additionally, the ETR mRNA expression was analyzed using quantitative real-time-PCR.ResultsThe mRNA of ETA but not ETB receptors was significantly elevated in heart failure, whereas total ETR density analyzed by radioligand binding was significantly reduced due to ETB receptor down regulation. ETA and ETB receptor density showed poor correlation to mRNA data (spearman correlation factor: 0.43 and 0.31, respectively). VAD support had no significant impact on the density of both receptors and on mRNA expression of ETA whereas ETB mRNA increased during VAD. A meta-analysis reveals that the ETA receptor regulation in human heart failure appears to depend on non-failing hearts.ConclusionsIn deteriorating hearts of patients suffering from dilated cardiomyopathy the ETA receptor density is not changed whereas the ETB receptor is down regulated. The mRNA and the proteins of ETA and ETB show a weak correlation. Non-failing hearts might influence the interpretation of ETA receptor regulation. Mechanical unloading of the failing hearts has no impact on the myocardial ETR density.

Highlights

Endothelins have been described as potent vasoconstrictor peptides consisting of 21 amino acids secreted by the endothelium [1]
In paired left ventricular samples of 12 dilated cardiomyopathy patients we investigated the density of endothelin A (ETA) and B (ETB) receptors before ventricular assist devices (VAD) implantation and after device removal
The mRNA of endothelin receptor A (ETA) but not ETB receptors was significantly elevated in heart failure, whereas total Endothelin receptor (ETR) density analyzed by radioligand binding was significantly reduced due to ETB receptor down regulation

Summary

Introduction

Endothelins have been described as potent vasoconstrictor peptides consisting of 21 amino acids secreted by the endothelium [1]. ET-1, the principal isoform is secreted by many cell types beyond endothelial cells including cardiac myocytes [3, 4]. Endothelins mediate their activity mainly in an autocrine/paracrine manner [5, 6] on its receptors of which two have been identified, named endothelin receptor A (ETA) and B (ETB). Endothelin receptors are G-protein-coupled receptors and mediate their action essentially in a phospholipase C dependent manner. They are expressed in a variety of tissues including the myocardium. The cardiac ETR regulation in human heart failure and during VAD support is incompletely understood

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