Modulating fatty acid metabolism in pathological cardiac hypertrophy
Final Report Abstract
Increasing fatty acid oxidation (FAO) by cardiac-specific deletion of acetyl-CoA carboxylase (ACC2) has been shown to attenuate metabolic remodeling during chronic pressure overload, improve cardiac energetics, protect against cardiomyocyte hypertrophy and maintain cardiac function. Based on these data, two major goals were investigated in this research proposal: 1) to determine the mechanisms by which sustaining myocardial FAO protects against cardiac hypertrophy and 2) to test whether upregulating FAO can reverse the pathological remodeling and transition to heart failure. We found that ACC2 KD in isolated cardiomyocytes was able to recapitulate the in vivo phenotype and to prevent cardiomyocyte hypertrophy. Maintaining FAO suppressed increase utilization of glucose and upregulation of glycolysis, despite persistent activation of pro-growth signaling pathways. ACC2 KD further reduced glutamine consumption and intracellular aspartate accumulation. All three substrates have been shown to be required for cell growth in vitro and in vivo and ongoing research focusses on the exact interplay of these substrates and their contribution to cardiac growth. To determine the therapeutic potential of increasing FAO in vivo, mice were subjected to chronic pressure overload. After establishment of cardiac hypertrophy, when FAO was reduced in control hearts, ACC2 deletion was induced, which normalized FAO. However, ACC2 KO mice developed Creinduced cardiomyopathy and accelerated cardiac dysfunction, rendering this model unsuitable to answer the initial question.
Publications
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Metabolism in cardiomyopathy: every substrate matters. Cardiovasc Res. 2017 Mar 15;113(4):411-421
Ritterhoff J, Tian R
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Glucose Promotes Cell Growth by Suppressing Branched-chain Amino Acid Degradation. Nature Communications, Vol. 9. 2018, Article number: 2935.
Shao D., Villet O., Zhang Z., Choi S.W., Yan J., Ritterhoff J., Gu H., Djukovic D., Christodoulou D., Kolwicz Jr. S., Raftery D., Tian R.
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Fatty Acids Affect the Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells. Stem Cell Reports, Vol. 13. 2019, Issue 4, pp. 657-668.
Yang X., Rodriguez M., Leonard A., Sun L., Fischer K.A., Ritterhoff J., Zhao L., Kolwicz Jr. S., Pabon L., Reinecke H., Sniadecki N.J., Tian R., Ruohola-Baker H., Xu H., Murry C.E.
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Metabolic remodeling promotes cardiac hypertrophy by directing glucose to aspartate biosynthesis. Circulation Research, Vol. 126. 2020, Issue 2, pp. 182–196.
Ritterhoff J., Young S., Villet O., Shao D., Carnevale Neto F., Bettcher L.F., Hsu Y.W., Kolwicz S. Jr., Raftery D., Tian R.
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Increasing fatty acid oxidation elicits a sex-dependent response in failing mouse hearts. Journal of Molecular and Cellular Cardiology, Vol. 158. 2021, pp. 1-10.
Ritterhoff J., McMillen T., Villet O., Young S., Kolwicz J. S.C., Senn T., Caudal A., Tian R.
