title: Malonyl-CoA decarboxylase inhibition as a novel approach to treat ischemic heart disease.
abstract: BACKGROUND
  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.
  
  
  METHODS
  One approach to increasing pyruvate 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 pyruvate 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 pyruvate oxidation.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Research Group, 423 Heritage Medical Research Building, The University of Alberta, Edmonton, AL, T6G 2S2, Canada. gary.lopaschuk@ualberta.ca
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D004791:Enzyme Inhibitors; D005227:Fatty Acids; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase