© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Pulmonary endothelinergic system in experimental congestive heart failure
aINSERM U460, UFR X. Bichat, 16 rue Henri Huchard, 75018 Paris, France
bINSERM U36, Collège de France, 75005 Paris, France
cE 9920 INSERM VACOMED, Department of Pharmacology, Rouen, France
* Corresponding author. Tel.: +33-14-485-6152; fax: 33-14-485-6157 u460{at}bichat.inserm.fr
Objectives: 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. Methods and 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 ETB receptor mRNA in the congestive lung was significantly lower than in control and compensated HF rats (P<0.0001), while the expression of ETA 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/ETB receptor mRNA. Conclusion: Taken together, these data suggest that overexpression of ET-1 and down-regulation of ETB 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.
KEYWORDS Endothelins; Gene expression; Heart failure; Receptors
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