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Expression of endothelin-1, endothelin-converting enzyme, and endothelin receptors in chronic heart failure
1Zentrum für Innere Medizin, Klinik III für Innere Medizin, Universität zu Köln, Cologne, Germany.
Insights
In end-stage heart failure, endothelin (ET)-1 levels increase in the heart. Receptor expression shifts towards ETA, suggesting altered ET system activation in failing hearts.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Biochemistry
Background:
- Elevated plasma endothelin (ET)-1 is linked to heart diseases like heart failure.
- ET-1 may act locally in the heart, influencing vasoconstriction, cell growth, and contractility.
Purpose of the Study:
- To investigate changes in ET-1, ET receptor, and endothelin-converting enzyme (ECE) expression in the heart's left ventricle of heart failure patients.
Main Methods:
- Compared mRNA levels of ET receptors (ETA, ETB), prepro-ET-1 (ppET-1), and ECE in failing (dilated cardiomyopathy) and non-failing hearts using RT-PCR.
- Assessed ET receptor density via radioligand binding assays.
- Measured ECE activity and protein levels, and ET-1 concentrations.
Main Results:
- Reduced ETB receptor mRNA and protein density observed in failing hearts.
- Increased ETA receptor density in failing hearts.
- Elevated immunoreactive ET-1 concentrations in failing hearts, with unchanged ppET-1 and ECE expression/activity.
Conclusions:
- Human end-stage heart failure shows altered ET receptor expression favoring ETA.
- The cardiac ET system is activated in failing myocardium, indicated by increased ET-1.
- Increased ET-1 is likely due to reduced clearance rather than increased synthesis.
Background:
Elevated plasma levels of endothelin (ET)-1 have been reported in association with heart diseases, including heart failure. Furthermore, it has been suggested that ET-1 acts as a local autocrine/paracrine factor with biological activities such as vasoconstriction, mitogenesis, and inotropic effects on the heart. This study investigated alterations of ET-1, ET receptor, and endothelin-converting enzyme (ECE) expression in left ventricular myocardium from patients with end-stage heart failure.
Methods And Results:
mRNA concentrations of ETA and ETB receptors, prepro-ET-1 (ppET-1), and ECE in left ventricles from nonfailing donors hearts (NF) and from patients with end-stage chronic heart failure (NYHA functional class IV) due to dilated cardiomyopathy (DCM) were compared by use of a competitive reverse transcription-polymerase chain reaction technique. There was no significant difference in mRNA expression for ppET-1, ECE-1, and ETA receptors, whereas a significant reduction of ETB-receptor mRNA was observed in DCM hearts. 125I-labeled ET-1 radioligand binding studies demonstrated a significant downregulation of ETB receptors, whereas ETA-receptor density was increased in membranes from DCM hearts. Phosphoramidon-sensitive ECE activity and immunodetectable amounts of ECE protein in left ventricular membrane preparations did not differ between NF and DCM hearts. Finally, immunoreactive ET-1 concentrations were increased in DCM hearts.
Conclusions:
The present study demonstrates changes in the ET-receptor expression pattern in favor of the ETA receptor in human end-stage heart failure. Furthermore, activation of the cardiac ET system with increased tissue ET-1 concentrations in the failing myocardium is observed. This is more likely due to decreased clearance than to increased synthesis, because ppET-1 gene expression and ECE activity are unchanged.
