Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

Oka, Tatsujiro; Lam, Victoria; Zhang, Liyan; Keung, Wendy; Cadete, Virgilio J. J.; Samokhvalov, Victor; Tanner, Brandon; Beker, Donna L.; Ussher, John R.; Huqi, Alda; Jaswal, Jagdip S.; Rebeyka, Ivan M.; Lopaschuk, Gary D.

doi:10.1152/ajpheart.00804.2011

Cited by 19 publications

(36 citation statements)

References 47 publications

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“…Palmitate oxidation, glycolysis, lactate oxidation, and glucose oxidation rates were measured using radiolabeled [9, H]palmitate, [5- C]glucose, respectively, as described previously (16). Steady-state rates of ATP production from exogenous substrates were calculated with the values of 2, 15, 31, and 105 mol ATP/mol of glucose produced from glycolysis, lactate oxidation, glucose oxidation, and palmitate oxidation, respectively (44).…”

Section: Methodsmentioning

confidence: 99%

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Fukushima

Alrob

Zhang

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Fukushima A, Alrob OA, Zhang L, Wagg CS, Altamimi T, Rawat S, Rebeyka IM, Kantor PF, Lopaschuk GD. Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart. Am J Physiol Heart Circ Physiol 311: H347-H363, 2016. First published June 3, 2016; doi:10.1152/ajpheart.00900.2015.-Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid ␤-oxidation rates increased in 21-day vs. 1-and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and ␤-hydroxyacylCoA dehydrogenase (␤-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid ␤-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and ␤-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-␥ coactivator-1␣, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxiainducible factor-1␣, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation.Listen to this article's corresponding podcast at http://ajpheart.podbean. com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/. myocardial fatty acid oxidation; lysine acetylation; lysine succinylation; newborn heart NEW & NOTEWORTHYThe present study is the first showing that alterations in acetylation and succinylation control of metabolic enzymes contribute to the dramatic shift in cardiac energy metabolism from glycolysis to fatty acid ␤-oxidation seen during maturation. Our results suggest that lysine acetylation enhances cardiac fatty acid ␤-oxidation and inhibits glycolysis during maturation.OVER 1% OF NEWBORNS ARE DIAGNOSED with congenital heart disease (CHD), with one-third of these needing surgery within the first months of life (36). Despite the major advance...

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Section: Methodsmentioning

confidence: 99%

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Fukushima

Alrob

Zhang

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…18 The presence of a successful fistula was verified at postsurgical days 7 and 13 by color flow doppler that visualizes a physical shunt between the abdominal aorta and the inferior vena cava in both an axial and transverse plane. This is further validated by an enlarged inferior vena cava (an expanded Methods section is available in the Online Data Supplement).…”

Section: Assessment Of Myocardial Functionmentioning

confidence: 99%

“…Left ventricular ejection fraction (%) and other cardiac parameters were assessed by transthoracic echocardiography at postsurgical days 7 and 13 as described previously. 18 At 21 days of age (14 days post surgery), all animals were euthanized with Na + pentobarbital, and hearts were removed for isolated biventricular working heart perfusions.…”

Section: Assessment Of Myocardial Functionmentioning

confidence: 99%

“…16 Our previous reports demonstrate that volume-overload cardiac hypertrophy prevents the maturational increase in fatty acid oxidation seen postbirth partly due to higher malonyl-CoA levels, a potent endogenous CPT-I inhibitor, in neonatal pig and rabbit hearts. 17,18 As such, the hypertrophied myocardium retains a metabolic profile characteristic of the fetal heart. 17,18 Importantly, these alterations in energy substrate metabolism decrease the recovery of post-ischemic function, 18 whereas enhancing fatty acid β-oxidation by increasing substrate supply is cardioprotective in neonatal rabbit hearts.…”

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confidence: 99%

“…17,18 As such, the hypertrophied myocardium retains a metabolic profile characteristic of the fetal heart. 17,18 Importantly, these alterations in energy substrate metabolism decrease the recovery of post-ischemic function, 18 whereas enhancing fatty acid β-oxidation by increasing substrate supply is cardioprotective in neonatal rabbit hearts. 19 One potential approach to increasing fatty acid oxidation in the neonatal heart is through activation of PPARα by GW7647, a potent and selective PPARα activator.…”

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Activating PPARα Prevents Post–Ischemic Contractile Dysfunction in Hypertrophied Neonatal Hearts

Lam

Zhang

Huqi

et al. 2015

Circulation Research

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Rationale: Post-ischemic contractile dysfunction is a contributor to morbidity and mortality after the surgical correction of congenital heart defects in neonatal patients. Pre-existing hypertrophy in the newborn heart can exacerbate these ischemic injuries, which may partly be due to a decreased energy supply to the heart resulting from low fatty acid β-oxidation rates.Objective: We determined whether stimulating fatty acid β-oxidation with GW7647, a peroxisome proliferatoractivated receptor-α (PPARα) activator, would improve cardiac energy production and post-ischemic functional recovery in neonatal rabbit hearts subjected to volume overload-induced cardiac hypertrophy. Methods and Results:Volume-overload cardiac hypertrophy was produced in 7-day-old rabbits via an aorto-caval shunt, after which, the rabbits were treated with or without GW7647 (3 mg/kg per day) for 14 days. Biventricular working hearts were subjected to 35 minutes of aerobic perfusion, 25 minutes of global no-flow ischemia, and 30 minutes of aerobic reperfusion. GW7647 treatment did not prevent the development of cardiac hypertrophy, but did prevent the decline in left ventricular ejection fraction in vivo. GW7647 treatment increased cardiac fatty acid β-oxidation rates before and after ischemia, which resulted in a significant increase in overall ATP production and an improved in vitro post-ischemic functional recovery. A decrease in post-ischemic proton production and endoplasmic reticulum stress, as well as an activation of sarcoplasmic reticulum calcium ATPase isoform 2 and citrate synthase, was evident in GW7647-treated hearts. Conclusions:

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Malonyl CoA: A promising target for the treatment of cardiac disease

Fillmore

Lopaschuk

2014

IUBMB Life

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Alterations in cardiac energy metabolism are an important contributor to the high incidence and severity of heart disease in the world. These alterations can include an impairment of the production of ATP necessary to meet the high energy demands of the heart, as well as adverse switches in energy substrate preference by the heart. With regard to this latter point, evidence suggests that a decrease in cardiac efficiency, caused by a rise in cardiac fatty acid oxidation and/or an increase in the uncoupling of glycolysis from glucose oxidation, impairs cardiac function and is a contributing factor to cardiac disease. In support of this concept, therapeutic strategies that modulate these metabolic pathways and increase cardiac efficiency produce beneficial results in the setting of heart disease. One such strategy is to increase cardiac malonyl CoA levels, an important inhibitor of mitochondrial fatty acid uptake. This includes malonyl CoA decarboxylase (MCD) inhibition that results in increased cardiac malonyl CoA levels, decreased cardiac fatty acid oxidation rates, and improved cardiac efficiency. Preclinical studies have shown that MCD inhibition can improve cardiac function in various forms of heart disease. Here, we focus on the importance of malonyl CoA in the regulation of cardiac energy metabolism and function in the normal and diseased heart and discuss the evidence that suggests that inhibition of fatty acid oxidation especially via regulation of malonyl CoA, through MCD inhibition, is a promising strategy to treat cardiac disease.

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Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

Cited by 19 publications

References 47 publications

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Activating PPARα Prevents Post–Ischemic Contractile Dysfunction in Hypertrophied Neonatal Hearts

Malonyl CoA: A promising target for the treatment of cardiac disease

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