TY - JOUR
T1 - Selective upregulation of endothelin converting enzyme-1a in the human failing heart
AU - Ergul, Adviye
AU - Grubbs, A. L.
AU - Zhang, Y.
AU - Spinale, F. G.
N1 - Funding Information:
Supported in part by an American Lung Association of South Carolina Career Investigator Award (A.E.), Charleston, SC; American Diabetes Association Research Award (A.E.), New York, NY; and National Institutes of Health grant no. HL57952 (F.G.S.), Bethesda, Maryland. Manuscript received April 10, 2000; revised manuscript received June 19, 2000; revised manuscript accepted June 20, 2000. Reprint requests: Adviye Ergul, MD, PhD, Division of Cardiothoracic Surgery, 770 MUSC Complex, Suite 625, PO Box 250778, 114 Doughty Street, Charleston, SC 29425. Copyright © 2000 by Churchill Livingstone® 1071-9164/00/0604-0005$10.00/0 doi:10.1054/jcaf.2000.19227
PY - 2000
Y1 - 2000
N2 - 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. Methods and 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.
AB - 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. Methods and 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.
KW - Cardiomyopathy
KW - Congestive heart failure
KW - Myocardium
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U2 - 10.1054/jcaf.2000.19227
DO - 10.1054/jcaf.2000.19227
M3 - Article
C2 - 11145756
AN - SCOPUS:0034526430
SN - 1071-9164
VL - 6
SP - 314
EP - 320
JO - Journal of Cardiac Failure
JF - Journal of Cardiac Failure
IS - 4
ER -