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 r eperfusion of ischemic hearts could be explained by a decrease in malo nyl-CoA levels, which would relieve inhibition of carnitine palmitoylt ransferase 1, the rate limiting enzyme involved in mitochondrial uptak e of fatty acids. Isolated working rat hearts perfused with 1.2 mM pal mitate 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 hear ts, despite the fact that cardiac work recovered to only 16% of pre-is chemic values. Neither the activity of carnitine palmitoyltransferase 1, or the IC50 value of malonyl-CoA for carnitine palmitoyl transferas e 1 were altered in mitochondria isolated from aerobic, ischemic, or r eperfused ischemic hearts. Levels of malonyl-CoA were extremely low at the end of reperfusion compared to levels seen in aerobic controls, a s was the activity of acetyl-CoA carboxylase, the enzyme which produce s 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 th at 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 l result in accelerated fatty acid oxidation rates during reperfusion of ischemic hearts.