title: Regulation of cardiac malonyl-CoA content and fatty acid oxidation during increased cardiac power.
abstract: Myocardial fatty acid oxidation is regulated by carnitine palmitoyltransferase I (CPT I), which is inhibited by malonyl-CoA. Increased cardiac power causes a fall in malonyl-CoA content and accelerated fatty acid oxidation; however, the mechanism for the decrease in malonyl-CoA is unclear. Malonyl-CoA is formed by acetyl-CoA carboxylase (ACC) and degraded by malonyl-CoA decarboxylase (MCD); thus a fall in malonyl-CoA could be due to activation of MCD, inhibition of ACC, or both. This study assessed the effects of increased cardiac power on malonyl-CoA content and ACC and MCD activities. Anesthetized pigs were studied under control conditions and during increased cardiac power in response to dobutamine infusion and aortic constriction alone, under hyperglycemic conditions, or with the CPT I inhibitor oxfenicine. An increase in cardiac power was accompanied by increased myocardial O(2) consumption, decreased malonyl-CoA concentration, and increased fatty acid oxidation. There were no differences among groups in activity of ACC or AMP-activated protein kinase (AMPK), which physiologically inhibits ACC. There also were no differences in V(max) or K(m) of MCD. Previous studies have demonstrated that AMPK can be inhibited by protein kinase B (PKB); however, PKB was activated by dobutamine and the elevated insulin that accompanied hyperglycemia, but there was no effect on AMPK activity. In conclusion, the fall in malonyl-CoA and increase in fatty acid oxidation that occur with increased cardiac work were not due to inhibition of ACC or activation of MCD, suggesting alternative regulatory mechanisms for the work-induced decrease in malonyl-CoA concentration.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4970, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: King
authors.forename: Isidore C
authors.initials: IC
authors.lastname: Okere
authors.forename: Naveen
authors.initials: N
authors.lastname: Sharma
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Aneta E
authors.initials: AE
authors.lastname: Reszko
authors.forename: Tracy A
authors.initials: TA
authors.lastname: McElfresh
authors.forename: Janos
authors.initials: J
authors.lastname: Kerner
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D001794:Blood Pressure; D002316:Cardiotonic Agents / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D006339:Heart Rate; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034421:Sus scrofa
chemical_list: D002316:Cardiotonic Agents; D005227:Fatty Acids; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D004280:Dobutamine; D008316:Malonyl Coenzyme A; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases