title: Pulmonary endothelinergic system in experimental congestive heart failure.
abstract: OBJECTIVE
  Endothelin-1 (ET-1), plays an important role in the pathophysiology of CHF and the pulmonary endothelium is an early hemodynamic target in diastolic left ventricular dysfunction. Therefore we hypothesized that the lung is a main source of humoral endothelin in CHF and that its secretion is proportional to the degree of heart failure.
  
  
  RESULTS
  We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure, depending on infarct size. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that in the lung, the expression of preproET-1 mRNA was higher in decompensated HF than in control and compensated HF rats (P<0.001). Run-on assay demonstrated that ET-1 overexpression is regulated at a transcriptional level (P<0.01). In contrast, there was no change in ET-1 mRNA expression in aortae, left ventricular myocardium and skeletal muscle. The expression of endothelin-converting enzyme (ECE)-1 mRNA was not modified and the expression of ET(B) receptor mRNA in the congestive lung was significantly lower than in control and compensated HF rats (P<0.0001), while the expression of ET(A) receptor mRNA did not differ between groups. The lung and plasma ET-1 peptide levels were respectively 4.2 and 9 fold higher in the rats with decompensated HF than in control rats (P<0.05; P<0.0001). Organoculture experiments showed that the lung ET-1 peptide secretion level in rats with decompensated HF was higher than that in control rats (P<0.01). In contrast, there was no change in ET-1 peptide secretion by the left ventricular myocardium and skeletal muscle. In plasma of rats with decompensated HF, the rate of bigET-1 conversion to ET-1 was 22%. ET-1 peptide was also present in the pleural effusion of decompensated heart failure. Plasma ET-1 concentration was significantly correlated with upstream markers of left ventricular diastolic dysfunction, with the expression of preproET-1 mRNA in the lung, with lung and pleural ET-1 concentration and with the expression ratio of ET-1/ET(B) receptor mRNA.
  
  
  CONCLUSIONS
  Taken together, these data suggest that overexpression of ET-1 and down-regulation of ET(B) receptors in the lung are determinants of circulating endothelin in CHF. As a corollary, increased plasma endothelin may provide evidence of pulmonary endothelial dysfunction in CHF.
authors.affiliation: INSERM U460, UFR X. Bichat, 16 rue Henri Huchard, 75018, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Lepailleur-Enouf
authors.forename: G
authors.initials: G
authors.lastname: Egidy
authors.forename: M
authors.initials: M
authors.lastname: Philippe
authors.forename: L
authors.initials: L
authors.lastname: Louedec
authors.forename: J
authors.initials: J
authors.lastname: Henry
authors.forename: P
authors.initials: P
authors.lastname: Mulder
authors.forename: J
authors.initials: J
authors.lastname: Michel
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases; D018482:Muscle, Skeletal / Q000378:metabolism; D009924:Organ Culture Techniques; D010996:Pleural Effusion / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes