title: Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure.
abstract: Free fatty acid (FFA) oxidation is depressed in severe heart failure due to reduced activity of mitochondrial fatty acid oxidation enzymes. It is unknown whether the concomitant enhancement in cardiac glucose use is a consequence of reduced FFA oxidation, or also due to potentiation of the carbohydrate oxidative pathway. FFA and glucose oxidation rates were measured in vivo in 9 normal dogs and 9 dogs with pacing-induced heart failure by infusing (3)H-oleate and (14)C-glucose. FFA oxidation was lower (39 +/- 9 vs. 73 +/- 5 nmol min(-1) g(-1)), while glucose oxidation was higher (42 +/- 8 vs. 17 +/- 6 nmol min(-1) g(-1)) in failing compared to normal hearts (P < 0.05). At the end of the in vivo experiment, clamp-frozen biopsies were harvested from the left ventricle. Messenger RNAs encoding for proteins involved in both glucose and fatty acid metabolism, and for citrate synthase, were significantly reduced. Protein expression of GLUT-1 and GLUT-4, and GLUT-4 translocation to the sarcolemma showed no significant differences between the two groups despite a significant reduction in mRNAs with heart failure. GAPDH mRNA, protein expression, and activity were all reduced. The E2 subunit of pyruvate dehydrogenase was decreased both at the mRNA and protein level, with no effect on either fractional or maximal activity. In conclusion, we found either no changes or moderate downregulation of key enzymes of the carbohydrate metabolism in failing hearts, which suggests that the increase in glucose oxidation in vivo was principally due to impaired FFA oxidation and that the maximal myocardial capacity to obtain energy from substrate is globally depressed.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Lei
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lionetti
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Chiara
authors.initials: C
authors.lastname: d'Agostino
authors.forename: Elaine
authors.initials: E
authors.lastname: Kang
authors.forename: Martin
authors.initials: M
authors.lastname: Altarejos
authors.forename: Ken
authors.initials: K
authors.lastname: Matsuo
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Recchia
mesh_terms: D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000378:metabolism; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004285:Dogs; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006321:Heart / Q000502:physiology; D006331:Heart Diseases / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000473:pathology; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D019301:Oleic Acid / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D011485:Protein Binding; D020033:Protein Isoforms; D021381:Protein Transport; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors
chemical_list: D005227:Fatty Acids; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D019301:Oleic Acid; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D002950:Citrate (si)-Synthase; D005947:Glucose; D010100:Oxygen