title: Decreased long-chain fatty acid oxidation impairs postischemic recovery of the insulin-resistant rat heart.
abstract: Diabetic patients with acute myocardial infarction are more likely to die than nondiabetic patients. In the present study we examined the effect of insulin resistance on myocardial ischemia tolerance. Hearts of rats, rendered insulin resistant by high-sucrose feeding, were subjected to ischemia/reperfusion ex vivo. Cardiac power of control hearts from chow-fed rats recovered to 93%, while insulin-resistant hearts recovered only to 80% (P<0.001 vs. control). Unexpectedly, impaired contractile recovery did not result from an impairment of glucose oxidation (576±36 vs. 593±42 nmol/min/g dry weight; not significant), but from a failure to increase and to sustain oxidation of the long-chain fatty acid oleate on reperfusion (1878±56 vs. 2070±67 nmol/min/g dry weight; P<0.05). This phenomenon was due to a reduced ability to transport oleate into mitochondria and associated with a 38-58% decrease in the mitochondrial uncoupling protein 3 (UCP3) levels. Contractile function was rescued by replacing oleate with a medium-chain fatty acid or by restoring UCP3 levels with 24 h of food withdrawal. Lastly, the knockdown of UCP3 in rat L6 myocytes also decreased oleate oxidation by 13-18% following ischemia. Together the results expose UCP3 as a critical regulator of long-chain fatty acid oxidation in the stressed heart postischemia and identify octanoate as an intervention by which myocardial metabolism can be manipulated to improve function of the insulin-resistant heart.
authors.affiliation: 1University of Texas Medical School at Houston, 6431 Fannin, MSB 1.246, Houston, TX 77030, USA. heinrich.taegtmeyer@uth.tmc.edu.
authors.forename: Romain
authors.initials: R
authors.lastname: Harmancey
authors.forename: Hernan G
authors.initials: HG
authors.lastname: Vasquez
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Guthrie
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
mesh_terms: D000821:Animal Feed; D000818:Animals; D002210:Caprylates; D004032:Diet; D004040:Dietary Carbohydrates; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D013395:Sucrose; D000071247:Uncoupling Protein 3
chemical_list: D002210:Caprylates; D004040:Dietary Carbohydrates; D005227:Fatty Acids; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D013395:Sucrose; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; C031492:octanoic acid
keywords: cardiac function; high-sucrose diet; myocardial metabolism; type 2 diabetes; uncoupling proteins