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Cardiovascular Drugs and Therapy

, Volume 20, Issue 6, pp 433–439 | Cite as

Malonyl-CoA Decarboxylase Inhibition as a Novel Approach to Treat Ischemic Heart Disease

  • Gary D. Lopaschuk
  • William C. Stanley
Review

Abstract

Introduction

During and following cardiac ischemia the levels of circulating fatty acids are elevated, resulting in fatty acid oxidation dominating as a source of oxidative metabolism at the expense of pyruvate oxidation. A decrease in the levels of myocardial malonyl-CoA (an endogenous inhibitor of mitochondrial fatty acid uptake) contributes to these high fatty acid oxidation rates. Low pyruvate oxidation rates during and following ischemia results in the accumulation of metabolic byproducts (lactate and protons) that leads to impaired cardiac function, decreased cardiac efficiency, and increased myocardial tissue injury.

Methodology

One approach to increasing pyrvuate oxidation during and following ischemia is to inhibit fatty acid oxidation, which results in an improvement of both cardiac function and cardiac efficiency. A novel approach to decreasing fatty acid oxidation and increasing pyrvuate oxidation is to increase myocardial levels of malonyl-CoA. This can be achieved by pharmacologically inhibiting malonyl-CoA decarboxylase (MCD), the principal enzyme involved in the degradation of cardiac malonyl-CoA.

Results

Studies with either genetic deletion of MCD in the mouse or with novel MCD inhibitors show that decreased MCD activity increases cardiac malonyl-CoA, resulting in an inhibition of fatty acid oxidation and a stimulation of pyrvuate oxidation.

Conclusion

The beneficial effects of MCD inhibition on cardiac function and cardiac efficiency suggest that this approach could be an effective means to treat ischemic heart disease.

Key words

malonyl-CoA decarboxylase ischemia reperfusion 

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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  1. 1.Cardiovascular Research Group, 423 Heritage Medical Research BuildingThe University of AlbertaEdmontonCanada
  2. 2.Department of Physiology and BiophysicsCase Western UniversityClevelandUSA
  3. 3.Division of Cardiology, Department of MedicineUniversity of MarylandBaltimoreUSA

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