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Increased cardiac and pulmonary endothelin-1 mRNA expression in canine pacing-induced heart failure
K Huntington1, P Picard, G Moe
1Division of Cardiology, Terrence Donnelly Heart Center, St. Michael's Hospital, University of Toronto, Ontario, Canada.
Insights
Pacing-induced heart failure in dogs increases endothelin-1 (ET-1) gene expression in the lungs and left ventricle (LV). Blocking ET-1 receptors partially reduces pulmonary hypertension and LV dysfunction in this heart failure model.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- The canine model of pacing-induced heart failure (HF) mimics human dilated cardiomyopathy, showing significant hemodynamic changes.
- Previous studies indicated elevated plasma and tissue endothelin-1 (ET-1) levels in this model, but ET-1 gene expression remained uninvestigated.
Purpose of the Study:
- To investigate the gene expression of preproET-1 (the precursor to ET-1) in the left ventricle (LV) and lungs of dogs with pacing-induced HF.
- To determine the effect of ETA receptor antagonism on preproET-1 mRNA levels in this HF model.
Main Methods:
- Pacing-induced heart failure (pHF) was established in dogs over 3 weeks.
- PreproET-1 mRNA expression in LV and lung tissue was quantified using ribonuclease protection assay and densitometry.
- Dogs were treated with an ETA antagonist (LU135252) to assess its impact on hemodynamic parameters and gene expression.
Main Results:
- Pacing significantly increased mean pulmonary artery pressure and LV end-diastolic pressure.
- PreproET-1 mRNA expression was markedly elevated in both the LV and lungs of pHF dogs compared to controls.
- Treatment with LU135252 partially attenuated the increase in pulmonary artery pressure and LV end-diastolic pressure.
- The ETA antagonist reduced preproET-1 mRNA in the lungs but not in the LV of pHF dogs.
Conclusions:
- Increased pulmonary and LV preproET-1 gene expression in pacing-induced HF suggests a role for ET-1 in mediating pulmonary hypertension and LV dysfunction.
- ETA receptor blockade demonstrates a potential therapeutic avenue for managing specific aspects of this heart failure model.
Abstract:
The canine model of pacing-induced heart failure (HF) simulates human dilated cardiomyopathy and is characterized by severe hemodynamic perturbations. We have previously demonstrated increased plasma endothelin-1 (ET-1) and left ventricular (LV) tissue peptide levels in this model. However, the gene expression of ET-1 has not been studied. Accordingly, we compared preproET-1 mRNA in the lungs and LV in control normal dogs, dogs with severe HF after 3 weeks of rapid pacing (pHF), and pHF dogs chronically treated with an ETA antagonist, LU135252 (pHF-LU). PreproET-1 mRNA expression was determined by ribonuclease protection assay and quantified by densitometry. In paced dogs, mean pulmonary artery pressure (PA) and LV end-diastolic pressure (LVEDP) increased markedly from 16 +/- 4 and 8 +/- 3 mm Hg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mm Hg, respectively, at 3 weeks (both p < 0.001). Treatment with LU135252 attenuated the increase in PA and LVEDP by 30% and 19%, respectively (p < 0.05 for both). Compared to controls, preproET-1 mRNA expression in the LV and lungs was markedly increased in pHF. This was not changed in the LV but was reduced in the lungs by treatment with the ETA antagonist. Increased pulmonary and LV expression of preproET-1 suggests that ET-1 plays a role in mediating the pulmonary hypertension and LV dysfunction characteristic of this model.