Selective upregulation of endothelin converting enzyme-1a in the human failing heart.
BACKGROUND
Increased plasma levels of endothelin-1 (ET-1) occur with congestive heart failure (CHF), but the components of the enzymatic activation of ET-1 in the myocardium remain to be defined. Accordingly, endothelin converting enzyme-1 (ECE-1) activity and expression in normal and failing heart were examined.


RESULTS
Left ventricular (LV) tissue samples were obtained from patients undergoing heart transplantation because of dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) and from normal donor hearts. The gene expression of ET-1 precursor and ECE-1a was upregulated 4- and 3-fold, respectively, in the failing heart. ECE-1 activity (fmol/mg protein per hour) was augmented from 2,291+/-257 in normal tissue samples to 5,507+/-666 in DCM samples and to 7,435+/-682 in ICM samples (P < .05). Phosphoramidon and a specific ECE-1 inhibitor, FR901533, inhibited ECE-1 activity by over 90%. However, inhibitors of neutral endopeptidase (thiorphan) and matrix metalloproteases (batimistat) did not affect the conversion of big ET-1 to ET-1.


CONCLUSIONS
This study showed that the biosynthetic pathway of ET-1 is activated in LV myocardium in the failing heart, and the myocardial processing of big ET-1 is highly specific for ECE-1.
Ergul
A
A
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, USA.
Grubbs
A L
AL
Zhang
Y
Y
Spinale
F G
FG
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000150:complications; D016022:Case-Control Studies; D000072396:Endothelin-Converting Enzymes; D005786:Gene Expression Regulation / Q000502:physiology*; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013754:Tetracyclines / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D013754:Tetracyclines; D013876:Thiophenes; C088494:WS 79089B; D010649:Phenylalanine; C080985:batimastat; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes