title: Malonyl-CoA decarboxylase inhibition suppresses fatty acid oxidation and reduces lactate production during demand-induced ischemia.
abstract: The rate of cardiac fatty acid oxidation is regulated by the activity of carnitine palmitoyltransferase-I (CPT-I), which is inhibited by malonyl-CoA. We tested the hypothesis that the activity of the enzyme responsible for malonyl-CoA degradation, malonyl-CoA decarboxlyase (MCD), regulates myocardial malonyl-CoA content and the rate of fatty acid oxidation during demand-induced ischemia in vivo. The myocardial content of malonyl-CoA was increased in anesthetized pigs using a specific inhibitor of MCD (CBM-301106), which we hypothesized would result in inhibition of CPT-I, reduction in fatty acid oxidation, a reciprocal activation of glucose oxidation, and diminished lactate production during demand-induced ischemia. Under normal-flow conditions, treatment with the MCD inhibitor significantly reduced oxidation of exogenous fatty acids by 82%, shifted the relationship between arterial fatty acids and fatty acid oxidation downward, and increased glucose oxidation by 50%. Ischemia was induced by a 20% flow reduction and beta-adrenergic stimulation, which resulted in myocardial lactate production. During ischemia MCD inhibition elevated malonyl-CoA content fourfold, reduced free fatty acid oxidation rate by 87%, and resulted in a 50% decrease in lactate production. Moreover, fatty acid oxidation during ischemia was inversely related to the tissue malonyl-CoA content (r = -0.63). There were no differences between groups in myocardial ATP content, the activity of pyruvate dehydrogenase, or myocardial contractile function during ischemia. Thus modulation of MCD activity is an effective means of regulating myocardial fatty acid oxidation under normal and ischemic conditions and reducing lactate production during demand-induced ischemia.
authors.affiliation: Dept. of Physiology and Biophysics, School of Medicine, Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106-4970, USA. wcs4@case.edu
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
authors.forename: Eric E
authors.initials: EE
authors.lastname: Morgan
authors.forename: Hazel
authors.initials: H
authors.lastname: Huang
authors.forename: Tracy A
authors.initials: TA
authors.lastname: McElfresh
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Sterk
authors.forename: Isidore C
authors.initials: IC
authors.lastname: Okere
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Jiefei
authors.initials: J
authors.lastname: Cheng
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood*; D015227:Lipid Peroxidation / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D013552:Swine
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D019344:Lactic Acid; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase