Expression of endothelin-1, endothelin-converting enzyme, and endothelin receptors in chronic heart failure.
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.


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.
Zolk
O
O
Zentrum für Innere Medizin, Klinik III für Innere Medizin, Universität zu Köln, Cologne, Germany.
Quattek
J
J
Sitzler
G
G
Schrader
T
T
Nickenig
G
G
Schnabel
P
P
Shimada
K
K
Takahashi
M
M
Böhm
M
M
D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D009320:Atrial Natriuretic Factor / Q000235:genetics; D017931:DNA Primers; D015536:Down-Regulation; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D008666:Metalloendopeptidases; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011869:Radioligand Assay; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D017931:DNA Primers; D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011943:Receptors, Adrenergic, beta; D017466:Receptors, Endothelin; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes