HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 289/6/H2304    most recent 00599.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Stanley, W. C. Articles by Lopaschuk, G. D. Search for Related Content PubMed PubMed Citation Articles by Stanley, W. C. Articles by Lopaschuk, G. D.

TRANSLATIONAL PHYSIOLOGY

Malonyl-CoA decarboxylase inhibition suppresses fatty acid oxidation and reduces lactate production during demand-induced ischemia

¹Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio; ²Chugai Pharma USA, San Diego, California; and ³Department of Pediatrics, University of Alberta and ⁴Metabolic Modulators Research Ltd., Edmonton, Alberta, Canada

Submitted 6 June 2005 ; accepted in final form 5 August 2005

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 -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.

carnitine palmitoyltransferase-I; glucose; heart; lactate; myocardium

This article has been cited by other articles:

				L. Zhou, H. Huang, T. A. McElfresh, D. A. Prosdocimo, and W. C. Stanley Impact of anaerobic glycolysis and oxidative substrate selection on contractile function and mechanical efficiency during moderate severity ischemia Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H939 - H945. [Abstract] [Full Text] [PDF]

				J. R. Ussher and G. D. Lopaschuk The malonyl CoA axis as a potential target for treating ischaemic heart disease Cardiovasc Res, July 15, 2008; 79(2): 259 - 268. [Abstract] [Full Text] [PDF]

				L. Zhou, H. Huang, C. L. Yuan, W. Keung, G. D. Lopaschuk, and W. C. Stanley Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H954 - H960. [Abstract] [Full Text] [PDF]