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Maturation of Cardiac Energy Metabolism in the Normal and Hypertrophied Newborn Heart
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- Author / Creator
- Rawat, Sonia
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Dramatic maturational changes occur in heart energy metabolism in the fetal to newborn transition, most predominantly marked by a decrease in glycolysis and an increase in fatty acid oxidation which then becomes the major energy providing substrate for the heart after birth. However, in the presence of hypertrophy, this maturation of fatty acid oxidation is delayed; wherein the dramatic increase of fatty acid oxidation after birth does not occur. Without the increase in fatty acid oxidation, the heart is at risk of having a decreased energy capacity since fatty acids are the major energy providing substrate for these hearts. The underlying mechanisms for the increase in fatty acid oxidation shortly after birth and the delay in fatty acid oxidation in hypertrophied newborn hearts are not yet fully elucidated. The regulation of the maturation of newborn cardiac metabolism occurs at three levels: transcriptional control, allosteric control, and the most recently emerging is post-translational modifications (PTMs). PTMs can either activate or inhibit enzymatic activity of a protein. Previously, lysine acetylation was shown to activate cardiac fatty acid oxidative enzymes in obesity. Recently, metabolomics showed that the lysine PTM called succinylation is also important in regulating cardiac energy metabolism enzymes. However, the importance of acetylation and succinylation in the newborn setting of cardiac metabolism is unclear. We aim to investigate the role of acetylation and succinylation in the maturation of cardiac fatty acid metabolism and in hypertrophied newborn hearts. Also, in the case of hypoplastic left heart syndrome (HLHS), which is a severe congenital heart defect (CHD) consisting of underdevelopment of the left-sided cardiac structures, there may be cardiac metabolic abnormalities that differentiate this severe CHD from other types of CHDs. We aim to investigate the differences in metabolism between HLHS and non-HLHS patients. Hearts from rabbits aged 1-day, 7-days, and 21-days old underwent isolated heart perfusions and the frozen tissue was processed for Western blotting, immunoprecipitation, and enzymatic activity assays. Myocardial tissue obtained from infants aged 0-200 days old undergoing corrective heart surgery at the University of Alberta was used to analyze the succinylation status in these hearts and the status of metabolic proteins including protein abundance and acetylation of energy metabolic proteins in HLHS patients compared to non-HLHS patients. Also, 21-day old rabbit hearts with an aorto-caval shunt as a model for congenital heart defects and volume-overload hypertrophy were perfused in isolated biventricular working mode to measure flux through metabolic pathways and frozen tissue was used to investigate the role of acetylation and succinylation on fatty acid oxidation in hypertrophy. We observed that total acetylation and succinylation abundance of mitochondrial proteins increased consistently from 1-day to 21 days post-birth and this was correlated with an increase in palmitate oxidation rates. In 21-day old hypertrophied rabbit hearts, palmitate oxidation and ATP production rates were significantly lower compared to the sham group. Acetylation, but not succinylation, of fatty acid oxidation enzymes long chain acyl CoA dehydrogenase (LCAD) and b-hydroxyacyl CoA dehydrogenase (b-HAD) was also lower in the hypertrophied hearts compared to sham, and this acetylation was positively correlated with their enzymatic activity and palmitate oxidation rates. In human myocardial tissue, total lysine succinylation levels did not change with age, although there was a decrease in succinylation in the hypertrophied hearts compared to nonhypertrophied in the 101-200 day old group. In our study investigating HLHS infant hearts, transcriptional, allosteric, and post-translational control of fatty acid oxidation was not compromised in HLHS patients compared to non-HLHS patients. In fact, increased cardiac PGC1a protein levels suggested an increased ability for mitochondrial biogenesis in HLHS patients. Taken together we found that acetylation contributes to the normal increase of fatty acid oxidation in newborn hearts shortly after birth and to the delayed maturation of fatty acid oxidation in hypertrophied hearts. On the other hand, succinylation is another regulator of the maturation of fatty acid oxidation, having a stimulatory effect on LCAD, but the role of succinylation in hypertrophied hearts is less apparent although further studies in slightly older age groups is still required. HLHS infant hearts did not show compromised cardiac energetics and this may not be an important risk-factor in perioperative dysfunction of the right ventricle in newborns with HLHS.
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- Graduation date
- Spring 2019
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
- Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.