Selective upregulation of endothelin converting enzyme-1a in the human failing heart

Background: Increased plasma levels of endothelin-1 (ET-1) occur with conge stive heart failure (CHF), but the components of the enzymatic activation o f ET-1 in the myocardium remain to be defined. Accordingly, endothelin conv erting enzyme-1 (ECE-1) activity and expression in normal and failing heart were examined. Methods and Results: Left ventricular (LV) tissue samples were obtained fro m patients undergoing heart transplantation because of dilated cardiomyopat hy (DCM) and ischemic cardiomyopathy (ICM) and from normal donor hearts. Th e gene expression of ET-1 precursor and ECE-1a was upregulated 4- and 3-fol d, 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). Phospho r amidon 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 E T-1 to ET-1. Conclusions: This study showed that the biosynthetic pathway of ET-1 is act ivated in LV myocardium in the failing heart, and the myocardial processing of big ET-1 is highly specific for ECE-1.