Expression and activity of pulmonary endothelin converting enzyme in heart failure: relation to endothelin biosynthesis and receptor distribution

BACKGROUND: Although reduced pulmonary clearance of endothelin-1 (ET-1) has been suggested to contribute to increased circulating levels in congestive heart failure (CHF), the regulation of the pulmonary ET system with CHF remains to be defined. Accordingly, the aim of the present study is to investigate the expression and activity of the ET system with the development of CHF. METHODS AND RESULTS: Pulmonary tissue samples were collected from pigs with pacing CHF (240 bpm, 3 wks, n = 10) and controls (n = 10). The pulmonary messenger RNA (mRNA) and protein levels of endothelin converting enzyme-1 (ECE-1) subisoforms, ET-1, and ET receptor profiles were determined. The gene expression of ET-1 precursor, ECE-1a, and ET(A) was upregulated 4-, 3-, and 2-fold, respectively, with CHF. Pulmonary tissue ET-1 was increased to 13 +/- 2 fmol/mg protein from control values of 5 +/- 1 fmol/mg protein (P <.05), and ECE-1 activity was augmented from 3,264 +/- 665 fmol/mg protein in control animals to 14,073 +/- 654 fmol/mg protein per hour in CHF animals (P <.05). The ET(B) receptor density decreased, whereas ET(A) receptors were increased in CHF, indicating a shift in the ET(A) to ET(B) ratio. CONCLUSIONS: Both the increased synthesis and the decreased clearance of ET-1 via ET(B) receptors may contribute to the increased systemic and pulmonary ET-1 levels in CHF.