Pulmonary endothelinergic system in experimental congestive heart failure

Area of Science:

• Cardiovascular Physiology
• Pulmonary Medicine
• Molecular Biology

Background:

• Endothelin-1 (ET-1) is implicated in the pathophysiology of congestive heart failure (CHF).
• The pulmonary endothelium is an early hemodynamic target in diastolic left ventricular dysfunction.

Purpose of the Study:

• To investigate if the lung is a primary source of circulating endothelin in CHF.
• To determine if endothelin secretion is proportional to the severity of heart failure.

Main Methods:

• Utilized a rat model of compensated and decompensated heart failure induced by coronary artery ligation.
• Employed reverse transcriptase polymerase chain reaction (RT-PCR), run-on assays, and organoculture experiments to assess gene and peptide expression and secretion.
• Measured endothelin-1 (ET-1), endothelin-converting enzyme (ECE)-1, and ET(A)/ET(B) receptor mRNA and peptide levels in various tissues and plasma.

Main Results:

• Lung preproET-1 mRNA expression was significantly higher in decompensated heart failure (HF) rats, indicating transcriptional regulation of ET-1 overexpression.
• Lung and plasma ET-1 peptide levels were markedly elevated in decompensated HF, correlating with markers of diastolic dysfunction.
• Pulmonary ET(B) receptor mRNA expression was significantly downregulated in decompensated HF, while ET(A) receptor expression remained unchanged.

Conclusions:

• Overexpression of ET-1 and downregulation of ET(B) receptors in the lung are key determinants of elevated circulating endothelin in CHF.
• Increased plasma endothelin serves as a potential indicator of pulmonary endothelial dysfunction in CHF.
• The lung is a significant contributor to circulating endothelin in the context of heart failure.