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Endothelin-converting enzyme inhibition ameliorates angiotensin II-induced cardiac damage
Dominik N Muller1, Alexander Mullally, Ralf Dechend
1HELIOS Klinikum-Berlin, Franz Volhard Clinic and Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Abstract:
We tested the hypothesis that endothelin-converting enzyme (ECE) inhibition ameliorates end-organ damage in rats harboring both human renin and human angiotensinogen genes (dTGR). Hypertension develops in the animals, and they die by age 7 weeks of heart and kidney failure. Three groups were studied: dTGR (n=12) receiving vehicle, dTGR receiving ECE inhibitor (RO0687629; 30 mg/kg by gavage; n=10), and Sprague-Dawley control rats (SD; n=10) receiving vehicle, all after week 4, with euthanasia at week 7. Systolic blood pressure was not reduced by ECE inhibitor compared with dTGR (205+/-6 versus 206+/-6 mm Hg at week 7, respectively). In contrast, ECE inhibitor treatment significantly reduced mortality rate to 20% (2 of 10), whereas untreated dTGR had a 52% mortality rate (7 of 12). ECE inhibitor treatment ameliorated cardiac damage and reduced left ventricular ECE activity below SD levels. Echocardiography at week 7 showed reduced cardiac hypertrophy (4.8+/-0.2 versus 5.7+/-0.2 mg/g, P<0.01) and increased left ventricular cavity diameter (5.5+/-0.3 versus 3.1+/-0.1 mm, P<0.001) and filling volume (0.42+/-0.04 versus 0.16+/-0.06 mL, P<0.05) after ECE inhibitor compared with untreated dTGR. ECE inhibitor treatment also reduced cardiac fibrosis, tissue factor expression, left ventricular basic fibroblast growth factor mRNA levels, and immunostaining in the vessel wall, independent of high blood pressure. In contrast, the ECE inhibitor treatment showed no renoprotective effect. These data are the first to show that ECE inhibition reduces angiotensin II-induced cardiac damage.
Insights
Endothelin-converting enzyme (ECE) inhibition reduced mortality and cardiac damage in hypertensive rats. This treatment ameliorated cardiac hypertrophy and fibrosis, independent of blood pressure effects, but did not protect the kidneys.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Renal Physiology
Background:
- Hypertension-induced end-organ damage is a significant clinical concern.
- Endothelin-converting enzyme (ECE) plays a role in angiotensin II production.
- Genetic models of hypertension offer insights into disease mechanisms.
Purpose of the Study:
- To investigate the effects of ECE inhibition on end-organ damage in a rat model of severe hypertension.
- To determine if ECE inhibition can reduce cardiac and renal damage and improve survival.
Main Methods:
- UtilizeddTGR rats with human renin and angiotensinogen genes, developing severe hypertension and organ damage.
- Administered an ECE inhibitor (RO0687629) or vehicle from week 4 to week 7.
- Assessed mortality, blood pressure, cardiac function (echocardiography), cardiac damage markers, and renal parameters.
Main Results:
- ECE inhibition significantly reduced mortality from 52% to 20% in dTGR rats.
- Cardiac hypertrophy, fibrosis, and left ventricular dysfunction were ameliorated by ECE inhibition.
- ECE inhibitor treatment reduced cardiac ECE activity and cardiac fibrosis.
- No significant reduction in systolic blood pressure or renoprotective effects were observed.
Conclusions:
- ECE inhibition effectively reduces angiotensin II-induced cardiac damage and mortality in a severe hypertension model.
- Cardiac benefits of ECE inhibition are independent of blood pressure reduction.
- ECE inhibition does not provide renoprotection in this model, suggesting tissue-specific effects.