Recruitment of Compensatory Pathways to Sustain Oxidative Flux With Reduced Carnitine Palmitoyltransferase I Activity Characterizes Inefficiency in Energy Metabolism in Hypertrophied Hearts

Sorokina, Natalia; O’Donnell, J. Michael; McKinney, Ronald; Pound, Kayla M; Woldegiorgis, Gebre; LaNoue, Kathryn F.; Ballal, Kalpana; Taegtmeyer, Heinrich; Buttrick, Peter M.; Lewandowski, E. Douglas

doi:10.1161/circulationaha.106.668665

Cited by 173 publications

(255 citation statements)

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“…Cardiac hypertrophy from LVH was induced by constricting the transverse aorta (hemoclip) of 3-wkold male Sprague-Dawley rats as previously described (27,42,50). This banding procedure relies on the natural growth of the animal to produce a gradually increasing degree of aortic constriction.…”

Section: Methodsmentioning

confidence: 99%

“…Hearts were excised at 48 -72 after gene transfer and perfused in retrograde fashion with modified Krebs-Henseleit buffer as previously described [116 mM NaCl, 4 mM KCl, 1.5 mM CaCl 2, 1.2 mM MgSO4, and 1.2 mM NaH2PO4 equilibrated with 95% O2-5% CO2 with 0.4 mM of unlabeled palmitate/albumin complex (3:1 molar ratio) and 5 mM glucose] (27,42,50). The hydrostatic perfusion pressure was 100 cmH2O, and a water-filled latex balloon in the LV set to a diastolic pressure of 5-10 mmHg was connected to a pressure transducer and provided hemodynamic recordings (Powerlab, ADInstruments, Colorado Springs, CO).…”

Section: Methodsmentioning

confidence: 99%

“…31 P and 13 C NMR measurements were acquired by previously described methods (35,42,50). 13 C NMR spectra were collected in 2-min time blocks over the 40-min protocol, and 31 P NMR spectra were each collected over 2-min intervals.…”

Section: Methodsmentioning

confidence: 99%

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Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo

O’Donnell

Fields²,

Xu³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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O'Donnell JM, Fields A, Xu X, Chowdhury SA, Geenen DL, Bi J. Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo. Am J Physiol Heart Circ Physiol 295: H2483-H2494, 2008. First published October 24, 2008 doi:10.1152/ajpheart.01023.2008.-Adenoviral gene transfer of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)2a to the hypertrophic heart in vivo has been consistently reported to lead to enhanced myocardial contractility. It is unknown if the faster skeletal muscle isoform, SERCA1, expressed in the whole heart in early failure, leads to similar improvements and whether metabolic requirements are maintained during an adrenergic challenge. In this study, Ad.cmv.SERCA1 was delivered in vivo to aortic banded and shamoperated Sprague-Dawley rat hearts. The total SERCA content increased 34%. At 48 -72 h posttransfer, echocardiograms were acquired, hearts were excised and retrograded perfused, and hemodynamics were measured parallel to NMR measures of the phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) and energy substrate selection at basal and high workloads (isoproterenol). In the Langendorff mode, the rate-pressure product was enhanced 27% with SERCA1 in hypertrophic hearts and 10% in shams. The adrenergic response to isoproterenol was significantly potentiated in both groups with SERCA1.31 P NMR analysis of PCr/ATP revealed that the ratio remained low in the hypertrophic group with SERCA1 overexpression and was not further compromised with adrenergic challenge.13 C NMR analysis revealed fat and carbohydrate oxidation were unaffected at basal with SERCA1 expression; however, there was a shift from fats to carbohydrates at higher workloads with SERCA1 in both groups. Transport of NADH-reducing equivalents into the mitochondria via the ␣-ketoglutamate-malate transporter was not affected by either SERCA1 overexpression or adrenergic challenge in both groups. Echocardiograms revealed an important distinction between in vivo versus ex vivo data. In contrast to previous SERCA2a studies, the echocardiogram data revealed that SERCA1 expression compromised function (fractional shortening) in the hypertrophic group. Shams were unaffected. While our ex vivo findings support much of the earlier cardiomyocyte and transgenic data, the in vivo data challenge previous reports of improved cardiac function in heart failure models after SERCA intervention. sarco(endo)plasmic reticulum Ca 2ϩ -ATPase; glucose oxidation; fatty acid oxidation; phosphocreatine-to-ATP ratio; myocardial energy potential THE CHANGES in intracellular Ca 2ϩ handling reported for the failing myocardium have been linked to sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA). Calcium uptake into the sarcoplasmic reticulum (SR) by SERCA determines the rate of calcium removal for relaxation, the SR calcium content, and calcium released for contractions (33,45). In the failing heart, it has been proposed that SERCA contributes to reduced contractil...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo

O’Donnell

Fields²,

Xu³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Mice subjected to 10 weeks of pressure overload developed cardiac hypertrophy, had lower rate pressure product compared with sham-operated mice, and were associated with decreased CPT1 activity and decreased palmitate oxidation rates. 80 Although the previous study examined cardiac metabolism in a mouse model with low fatty acid oxidation, Kolwicz et al 50 used a mouse model lacking ACC2 (ACC2 −/− ) in which higher cardiac fatty acid oxidation is found. Car-diac function was preserved in ACC2 −/− mice despite higher fatty acid oxidation rates.…”

Section: Cardiac Metabolism In Left Heart Failurementioning

confidence: 99%

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

Sankaralingam

Lopaschuk

2015

Pulm. circ.

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Pressure overload of the heart, such as seen with pulmonary hypertension and/or systemic hypertension, can result in cardiac hypertrophy and the eventual development of heart failure. The development of hypertrophy and heart failure is accompanied by numerous molecular changes in the heart, including alterations in cardiac energy metabolism. Under normal conditions, the high energy (adenosine triphosphate [ATP]) demands of the heart are primarily provided by the mitochondrial oxidation of fatty acids, carbohydrates (glucose and lactate), and ketones. In contrast, the hypertrophied failing heart is energy deficient because of its inability to produce adequate amounts of ATP. This can be attributed to a reduction in mitochondrial oxidative metabolism, with the heart becoming more reliant on glycolysis as a source of ATP production. If glycolysis is uncoupled from glucose oxidation, a decrease in cardiac efficiency can occur, which can contribute to the severity of heart failure due to pressure-overload hypertrophy. These metabolic changes are accompanied by alterations in the enzymes that are involved in the regulation of fatty acid and carbohydrate metabolism. It is now becoming clear that optimizing both energy production and the source of energy production are potential targets for pharmacological intervention aimed at improving cardiac function in the hypertrophied failing heart. In this review, we will focus on what alterations in energy metabolism occur in pressure overload induced left and right heart failure. We will also discuss potential targets and pharmacological approaches that can be used to treat heart failure occurring secondary to pulmonary hypertension and/or systemic hypertension.

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“…Therefore, LD-mTAG turnover couples and matches FA uptake to utilisation through both TAG synthesis and lipolysis, regulating energy provision and potentially cardiac function [118,161,163]. Failure of this dynamic relationship between exogenous FA metabolism and lipid deposition is a potential cause of the maladaptive changes that contribute to cardiac dysfunction [164].…”

mentioning

confidence: 99%

The role of triacylglycerol in cardiac energy provision

Evans

Hui‐Kang

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity.Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition. TAGs constitute potentially the major energy supply for working myocardium, both through bloodborne provision and as intracellular TAG within lipid droplets, but also provide the heart with fatty acids (FA) which the myocardium cannot itself synthesise but are required for glycerolipid derivatives with (non-energetic) functions, including membrane phospholipids and lipid signalling molecules. Furthermore they serve to buffer potentially toxic amphipathic fatty acid derivatives.Intracellular handling and disposition of TAGs and their FA and glycerolipid derivatives similarly requires dedicated mechanisms in view of their hydrophobic character. Dysregulation of utilisation can result in inadequate energy provision, accumulation of TAG and/or esterified species, and these may be responsible for significant cardiac dysfunction in a variety of disease states. This review will focus on the role of TAG in myocardial energy provision, by providing FAs from exogenous and endogenous TAG sources for mitochondrial oxidation and ATP production, and how this can change in disease and impact on cardiac function. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 3Key words:heart; triacylglycerol; very-low-density lipoprotein; VLDL; chylomicron; lipid droplet Highlights: Triacylglycerols are supplied to the myocardium within chylomicrons and VLDL  Heart assimilates triacylglycerol-rich lipoproteins by LPL and receptor-mediated routes  Exogenous triacylglycerol-derived fatty acids enter an intracellular lipid pool  Intracardiac triacylglycerol is an important source of fatty acids for oxidation  Dysregulation of triacylglycerol metabolism is associated with cardiac dysfunction

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Recruitment of Compensatory Pathways to Sustain Oxidative Flux With Reduced Carnitine Palmitoyltransferase I Activity Characterizes Inefficiency in Energy Metabolism in Hypertrophied Hearts

Cited by 173 publications

References 40 publications

Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo

Limited functional and metabolic improvements in hypertrophic and healthy rat heart overexpressing the skeletal muscle isoform of SERCA1 by adenoviral gene transfer in vivo

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

The role of triacylglycerol in cardiac energy provision

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