Tricarboxylic acid cycle activity in postischemic rat hearts.

Weiss, Robert G.; Kalil-Filho, R.; Herskowitz, Ahvie; Chacko, V. P.; Litt, Mortimer; Stern, Michael D.; Gerstenblith, Gary

doi:10.1161/01.cir.87.1.270

Cited by 37 publications

(15 citation statements)

References 51 publications

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“…Also, a source of acetyl-CoA other than pyruvate, either the medium chain fatty acid, octanoate, or the KB, AcAc, and BHB, was provided. Medium chain fatty acids is not subjected to carnitine palmitoyltransferase I regulation (41)(42)(43). Thus, the perfusate octanoate concentration sets the rate of mitochondrial acetyl-CoA generation.…”

Section: Resultsmentioning

confidence: 99%

A 13C Mass Isotopomer Study of Anaplerotic Pyruvate Carboxylation in Perfused Rat Hearts

Comte

Vincent

Bouchard

et al. 1997

Journal of Biological Chemistry

113

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Anaplerotic pyruvate carboxylation was examined in hearts perfused with physiological concentrations of glucose, [U-13 C 3 ]lactate, and [U-13 C 3 ]pyruvate. Also, a fatty acid, [1-13 C]octanoate, or ketone bodies were added at concentrations providing acetyl-CoA at a rate resulting in either low or substantial pyruvate decarboxylation. Relative contributions of pyruvate and fatty acids to citrate synthesis were determined from the 13 C labeling pattern of effluent citrate by gas chromatography-mass spectrometry (see companion article, Comte, B., Vincent, G., Bouchard, B., and Des Rosiers, C. (1997) J. Biol. Chem. 272, 26117-26124). Precision on flux measurements of anaplerotic pyruvate carboxylation depended on the mix of substrates supplied to the heart. Anaplerotic fluxes were precisely determined under conditions where acetyl-CoA was predominantly supplied by ␤-oxidation, as it occurred with 0.2 or 1 mM octanoate. Then, anaplerotic pyruvate carboxylation provided 3-8% of the OAA moiety of citrate and was modulated by concentrations of lactate and pyruvate in the physiological range. Also, the contribution of pyruvate to citrate formation through carboxylation was equal to or greater than through decarboxylation. Furthermore, 13 C labeling data on tissue citric acid cycle intermediates and pyruvate suggest that (i) anaplerosis occurs also at succinate and (ii) cataplerotic malate decarboxylation is low. Rather, the presence of citrate in the effluent perfusate of hearts perfused with physiological concentrations of glucose, lactate, and pyruvate and concentrations of octanoate leading to maximal oxidative rates suggests a cataplerotic citrate efflux from mitochondria to cytosol. Taken altogether, our data raise the possibility of a link between pyruvate carboxylation and mitochondrial citrate efflux. In view of the proposed feedback regulation of glycolysis by cytosolic citrate, such a link would support a role of anaplerosis and cataplerosis in metabolic signal transmission between mitochondria and cytosol in the normoxic heart.

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Section: Resultsmentioning

confidence: 99%

A 13C Mass Isotopomer Study of Anaplerotic Pyruvate Carboxylation in Perfused Rat Hearts

Comte

Vincent

Bouchard

et al. 1997

Journal of Biological Chemistry

113

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“…It has been speculated that anaplerotic flux may serve as a biosensor between the cytoplasm and the mitochondria (11,36,39,43,48). Furthermore, evidence suggests a role for anaplerosis in the regulation of contractile function in the heart (15,23,30,42,49). Recent studies have also shown that flux through pyruvate carboxylase regulates amino acid synthesis (33,34) and may be important in controlling cell growth (34,43).…”

Section: Discussionmentioning

confidence: 99%

IGF-I promotes a shift in metabolic flux in vascular smooth muscle cells

Hall

Gibbons

Chatham

2002

American Journal of Physiology-Endocrinology and Metabolism

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13C-nuclear magnetic resonance (NMR) spectroscopy was used to test our hypothesis that insulin-like growth factor I (IGF-I) stimulates glucose flux into both nonoxidative and oxidative pathways in vascular smooth muscle cells (VSMC). Rat VSMC were exposed to uniformly labeled [13C]glucose ([U-13C]glucose; 5.5 mM) and [3-13C]pyruvate (1 mM) in the presence and absence of IGF-I (100 ng/ml). IGF-I increased glucose flux through glycolysis and the tricarboxylic acid (TCA) cycle as well as total anaplerotic flux into the TCA cycle. Previous work in our laboratory identified an increase in GLUT1 content and glucose metabolism in neointimal VSMC that was sufficient to promote proliferation and inhibit apoptosis. To test whether IGF-I could potentiate the GLUT1-induced increased flux in the neointima, we utilized VSMC harboring constitutive overexpression of GLUT1. Indeed, IGF-I markedly potentiated the GLUT1-induced increase in glucose flux through glycolysis and the TCA cycle. Taken together, these findings demonstrate that upregulation of glucose transport through either IGF-I or increased GLUT1 content stimulates glucose flux through both nonoxidative and oxidative pathways in VSMC.

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“…The improvement in cardiac PCr/ATP with XOI is not likely due to an effect on infarct size because it is similar in control and infarcted hearts (Ref. 43, and see RESULTS) and because infarcted tissue does not contain significant PCr or ATP (45,48). XOI is one of the first metabolic interventions that normalize reduced cardiac energetics in any model of heart failure.…”

Section: Fig 1 Typical Transverse Short-axis 1 H Magnetic Resonancementioning

confidence: 94%

“…The PCr/ATP values were corrected for partial saturation effects using a factor determined in separate studies (6,8,46,47) that included fully relaxed acquisitions. Infarcted, nonviable myocardium lacks PCr and ATP (45,48). In prior 31 P MRS studies (16,18,19,32,33,37) of infarcted rodent hearts, the detected PCr and ATP signals were attributed to the surviving viable regions, even when the entire infarcted region was contained within the region studied by MRS. Based on this accepted practice and our efforts through animal positioning and slice selection to minimize infarcted tissue within the volume of interest, the cardiac PCr/ATP values reported here derive almost entirely from surviving, viable myocardium.…”

Section: In Micementioning

confidence: 97%

Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts

Naumova¹,

Chacko²,

Ouwerkerk³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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After myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In nonischemic heart failure, inhibition of xanthine oxidase (XO) improves mechanoenergetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOIs) have not been characterized in failing hearts after infarction. After undergoing permanent coronary ligation, mice received a XOI (allopurinol or oxypurinol) or matching placebo in the daily drinking water. Four weeks later, 1 H MRI and 31 P magnetic resonance spectroscopy (MRS) were used to quantify in vivo functional and metabolic changes in postinfarction remodeled mouse myocardium and the effects of XOIs on that process. End-systolic (ESV) and end-diastolic volumes (EDV) were increased by more than sixfold after infarction, left ventricle (LV) mass doubled (P Ͻ 0.005), and the LV ejection fraction (EF) decreased (14 Ϯ 9%) compared with control hearts (59 Ϯ 8%, P Ͻ 0.005) at 1 mo. The myocardial phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) was also significantly decreased in infarct remodeled hearts (1.4 Ϯ 0.6) compared with control animals (2.1 Ϯ 0.5, P Ͻ 0.02), in agreement with prior studies in larger animals. The XOIs allopurinol and oxypurinol did not change LV mass but limited the increase in ESV and EDV of infarct hearts by 50%, increased EF (23 Ϯ 9%, P ϭ 0.01), and normalized cardiac PCr/ATP (2.0 Ϯ 0.5, P Ͻ 0.04). We conclude that XOIs improve ventricular function after infarction and normalize high-energy phosphate ratio in heart failure. Thus XOI therapy offers a new and potentially complementary approach to limit the adverse contractile and metabolic consequences after infarction. postinfarction remodeled myocardium; cardiac metabolism; magnetic resonance spectroscopy; allopurinol VENTRICULAR REMODELING occurs after myocardial infarction (MI) in many species, including humans, and is typically characterized by progressive ventricular dilatation, eccentric hypertrophy, and contractile dysfunction (27,36,38). Patients with post-MI remodeling experience increased rates of heart failure and cardiovascular mortality, whereas interventions that reduce geometric ventricular remodeling improve outcomes (27,40,41,44). In addition to the geometric and contractile abnormalities associated with post-MI remodeling, adverse changes in energy metabolism also occur (15,29,32). Abnormalities in energy metabolism after MI include reductions in ATP, phosphocreatine (PCr), and in the activity of the creatine kinase (CK) reaction, the primary energy reserve reaction of the heart (20, 21, 29, 31). Inhibitors of CK significantly increase mortality after experimental infarction (16). The reduction in cardiac PCr-to-ATP ratio (PCr/ATP) in experimental postinfarction remodeling is similar to that observed in human heart failure, which, in turn, correlates with clinical severity and predicts overall and cardiovascular mortality (4,10,15, 31,34,49). Taken together, the ene...

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Tricarboxylic acid cycle activity in postischemic rat hearts.

Abstract: These results suggest that TCA cycle activity is not persistently decreased in dysfunctional reperfused myocardium after a brief ischemic episode and therefore cannot account for the reduced contractile function at that time.

Cited by 37 publications

References 51 publications

A 13C Mass Isotopomer Study of Anaplerotic Pyruvate Carboxylation in Perfused Rat Hearts

A 13C Mass Isotopomer Study of Anaplerotic Pyruvate Carboxylation in Perfused Rat Hearts

IGF-I promotes a shift in metabolic flux in vascular smooth muscle cells

Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts

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