Inhibition of very long chain acyl-CoA dehydrogenase during cardiac ischemia.
The heart utilizes primarily fatty acids for energy production. During ischemia, however, diminished oxygen supply necessitates a switch from beta-oxidation of fatty acids to glucose utilization and glycolysis. Molecular mechanisms responsible for these alterations in metabolism are not fully understood. Mitochondrial acyl-CoA dehydrogenase catalyzes the first committed step in the beta-oxidation of fatty acids. In the current study, an in vivo rat model of myocardial ischemia was utilized to determine whether specific acyl-CoA dehydrogenases exhibit ischemia-induced alterations in activity, identify mechanisms responsible for changes in enzyme function, and assess the effects on mitochondrial respiration. Very long chain acyl-CoA dehydrogenase (VLCAD) activity declined 34% during 30 min of ischemia. Loss in activity appeared specific to VLCAD as medium chain acyl-CoA dehydrogenase activity remained constant. Loss in VLCAD activity during ischemia was not due to loss in protein content. In addition, activity was restored in the presence of the detergent Triton X-100, suggesting that changes in the interaction between the protein and inner mitochondrial membrane are responsible for ischemia-induced loss in activity. Palmitoyl-carnitine supported ADP-dependent state 3 respiration declined as a result of ischemia. When octanoyl-carnitine was utilized state 3 respiration remained unchanged. State 4 respiration increased during ischemia, an increase that appears specific to fatty acid utilization. Thus, VLCAD represents a likely site for the modulation of substrate utilization during myocardial ischemia. However, the dramatic increase in mitochondrial state 4 respiration would be predicted to accentuate the imbalance between energy production and utilization.
Mason
Katherine E
KE
Division of Pediatric Pharmacology and Critical Care, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OH, USA. kxs2@cwru.edu
Stofan
Daniel A
DA
Szweda
Luke I
LI
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002331:Carnitine / Q000378:metabolism; D019069:Cell Respiration; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000473:pathology; D019308:Palmitic Acid / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D019308:Palmitic Acid; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine