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Selective endothelin receptor blockade reverses mitochondrial dysfunction in canine heart failure
José Marín-García1, Michael J Goldenthal, Gordon W Moe
1The Molecular Cardiology and Neuromuscular Institute, Highland Park, New Jersey 08904, USA.
Journal of Cardiac Failure
|November 2, 2002
Summary
Endothelin receptor blockade improved mitochondrial function in a canine model of congestive heart failure (CHF). This suggests a novel mechanism for ET(A) antagonist therapy in treating heart failure.
Area of Science:
- Biochemistry
- Cardiovascular Physiology
- Mitochondrial Biology
Background:
- Pacing-induced congestive heart failure (CHF) in canines shows reduced mitochondrial enzymatic activity in cardiac and skeletal muscles.
- Endothelin-1 (ET-1) plays a role in CHF pathogenesis, and ET-1 receptor blockade can slow disease progression.
Purpose of the Study:
- To investigate if ET-1 receptor blockade improves mitochondrial function in pacing-induced CHF.
- To test the hypothesis that improved mitochondrial function mediates the therapeutic effects of ET-1 receptor blockade.
Main Methods:
- Evaluated mitochondrial respiratory complex I-V and citrate synthase activity in myocardium and skeletal muscle.
- Compared paced animals with and without LU 135252, a selective endothelin type A (ET(A)) receptor antagonist.
Main Results:
- Specific activity of mitochondrial complexes V and III was significantly increased (50%-300%) in ET(A) antagonist-treated animals compared to untreated paced animals.
- Complex V and III activities were 65%-85% lower in both cardiac and skeletal muscle of untreated paced animals versus unpaced controls.
- Activities of complexes I, II, IV, and citrate synthase remained unchanged.
Conclusions:
- Endothelin activation may contribute to myocardial dysfunction and mitochondrial enzyme deficits in pacing-induced CHF.
- Enhanced mitochondrial function represents a potential novel mechanism underlying the benefits of ET(A) receptor blockade in CHF.