High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5'-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase.
We determined whether high fatty acid oxidation rates during aerobic reperfusion of ischemic hearts could be explained by a decrease in malonyl-CoA levels, which would relieve inhibition of carnitine palmitoyl-transferase 1, the rate-limiting enzyme involved in mitochondrial uptake of fatty acids. Isolated working rat hearts perfused with 1.2 mM palmitate were subjected to 30 min of global ischemia, followed by 60 min of aerobic reperfusion. Fatty acid oxidation rates during reperfusion were 136% higher than rates seen in aerobically perfused control hearts, despite the fact that cardiac work recovered to only 16% of pre-ischemic values. Neither the activity of carnitine palmitoyltransferase 1, or the IC50 value of malonyl-CoA for carnitine palmitoyl-transferase 1 were altered in mitochondria isolated from aerobic, ischemic, or reperfused ischemic hearts. Levels of malonyl-CoA were extremely low at the end of reperfusion compared to levels seen in aerobic controls, as was the activity of acetyl-CoA carboxylase, the enzyme which produces malonyl-CoA. The activity of 5'-AMP-activated protein kinase, which has been shown to phosphorylate and inactivate acetyl-CoA carboxylase in other tissues, was significantly increased at the end of ischemia, and remained elevated throughout reperfusion. These results suggest that accumulation of 5'-AMP during ischemia results in an activation of AMP-activated protein kinase, which phosphorylates and inactivates ACC during reperfusion. The subsequent decrease in malonyl-CoA levels wil result in accelerated fatty acid oxidation rates during reperfusion of ischemic hearts.
Kudo
N
N
Department of Pediatrics and Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, Canada.
Barr
A J
AJ
Barr
R L
RL
Desai
S
S
Lopaschuk
G D
GD
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D008297:Male; D008316:Malonyl Coenzyme A / Q000032:analysis / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000502:physiology*; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism; D010477:Perfusion; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017208:Rats, Wistar
D005227:Fatty Acids; D009097:Multienzyme Complexes; D010169:Palmitic Acids; D019308:Palmitic Acid; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase