title: Recruitment of NADH shuttling in pressure-overloaded and hypertrophic rat hearts.
abstract: Glucose metabolism in the heart requires oxidation of cytosolic NADH from glycolysis. This study examines shuttling reducing equivalents from the cytosol to the mitochondria via the activity and expression of the oxoglutarate-malate carrier (OMC) in rat hearts subjected to 2 wk (Hyp2, n = 6) and 10 wk (Hyp10, n = 8) of pressure overload hypertrophy vs. that of sham-operated rats (Sham2, n = 6; and Sham10, n = 7). Moderate aortic banding produced increased atrial natriuretic factor (ANF) mRNA expression at 2 and 10 wk, but only at 10 wk did hearts develop compensatory hypertrophy (33% increase, P < 0.05). Isolated hearts were perfused with the short-chain fatty acid [2,4-(13)C(2)]butyrate (2 mM) and glucose (5 mM) to enable dynamic-mode (13)C NMR of intermediate exchange across OMC. OMC flux increased before the development of hypertrophy: Hyp2 = 9.6 +/- 2.1 vs. Sham2 = 3.7 +/- 1.2 muM.min(-1).g dry wt(-1), providing an increased contribution of cytosolic NADH to energy synthesis in the mitochondria. With compensatory hypertrophy, OMC flux returned to normal: Hyp10 = 3.9 +/- 1.7 vs. Sham10 = 3.8 +/- 1.2 muM.g(-1).min(-1). Despite changes in activity, no differences in OMC expression occurred between Hyp and Sham groups. Elevated OMC flux represented augmented cytosolic NADH shuttling, coupled to increased nonoxidative glycolysis, in response to hypertrophic stimulus. However, development of compensatory hypertrophy moderated the pressure-induced elevation in OMC flux, which returned to control levels. The findings indicate that the challenge of pressure overload increases cytosolic redox state and its contribution to mitochondrial oxidation but that hypertrophy, before decompensation, alleviates this stress response.
authors.affiliation: Program in Integrative Cardiac Metabolism, 835 S. Wolcott Ave., MC901, University of Illinois, College of Medicine, Chicago, IL 60612, USA. dougl@uic.edu
authors.forename: E Douglas
authors.initials: ED
authors.lastname: Lewandowski
authors.forename: J Michael
authors.initials: JM
authors.lastname: O'donnell
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Scholz
authors.forename: Natalia
authors.initials: N
authors.lastname: Sorokina
authors.forename: Peter M
authors.initials: PM
authors.lastname: Buttrick
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure; D002087:Butyrates / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D004195:Disease Models, Animal; D006019:Glycolysis; D006339:Heart Rate; D006973:Hypertension / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D008026:Ligation; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D002087:Butyrates; D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D009243:NAD; C066909:2-oxoglutarate-malate carrier protein; D009320:Atrial Natriuretic Factor