Abstract 357: Branched-Chain Amino Acid Metabolic Reprogramming in Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Haipeng Sun ◽  
Kristine Olson ◽  
Meiyi Zhou ◽  
Domenick Prosdocimo ◽  
Chen Gao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Amino Acid ◽  
Building Blocks ◽  
Metabolic Reprogramming ◽  
Genetic Ablation ◽  
Failing Heart ◽  
Catabolic Genes ◽  
Metabolic Remodeling ◽  
Heart Failure Progression ◽  
Branched Chain

Metabolic remodeling is an integral part of heart failure. Current studies are largely focusing on glucose and fatty acid metabolism, while little is known about the changes in amino acid homeostasis during heart failing process. Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, serve as not only essential building blocks for protein synthesis, but also important energy source and signaling molecules that have significant effects on cell growth and function. In this study, we demonstrated that the BCAA catabolic intermediate branched-chain keto acid (BCKA) accumulated in both mouse and human failing heart. BCAA catabolic genes were selectively and significantly down-regulated at both mRNA and protein levels in failing heart in mice, mimicking a similar expression pattern observed in neonatal heart. Using both in vitro and in vivo models, we established that BCAA catabolic genes were regulated by Krüppel-like factor 15 (KLF15), a key transcriptional regulator for glucose, fat, and amino acid nutrient homeostasis, suggesting that the KLF15-mediated BCAA catabolic regulation is part of the metabolic remodeling during heart failure. Genetic ablation of PP2Cm, a key regulator of BCAA catabolism, led to a significant impairment of BCAA catabolic activities and accumulation of BCKA in cardiac tissue. Importantly, PP2Cm deficiency accelerated heart failure under pressure overload. PP2Cm deficiency or elevated BCKA induced oxidative stress in cardiomyocytes and impairment of oxygen consumption and ATP production of mitochondria. Antioxidant treatment ameliorated the heart failure progression in PP2Cm deficient animals. Taken together, our data established for the first time that BCAA catabolic reprogramming is an integral component of metabolic remodeling during heart failure, and this remodeling can significantly contribute to heart failure progression.

Abstract 183: Branched-Chain Amino Acid Catabolic Reprogramming in Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Haipeng Sun ◽  
Kristine Olson ◽  
Chen Gao ◽  
Domenick A Prosdocimo ◽  
Meiyi Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Amino Acid ◽  
Metabolic Diseases ◽  
Metabolic Reprogramming ◽  
Similar Expression Pattern ◽  
Metabolic Remodeling ◽  
Heart Failure Progression ◽  
Branched Chain

Abnormal branched-chain amino acids (BCAA) catabolism has been strongly linked with cardiovascular and metabolic diseases in recent studies. In heart, metabolic reprogramming associated with the onset of heart failure has been established based on fetal-like changes in fatty acid and glucose metabolism, while little is known about the changes in amino acid homeostasis. In this report, we demonstrated a signature of suppressed BCAA catabolism in failing rodent and human hearts. The branched-chain α-keto acids (BCKA), intermediate of BCAA catabolism, accumulates, closely coordinated with reduced expression of key enzymes of BCAA catabolism in pathologically stressed myocardium. The down-regulation of these genes mimics a similar expression pattern observed in neonatal heart, indicating a fetal-like genetic reprogramming. Using both in vitro and in vivo models, we identified KLF15 as a key transcriptional regulator of the BCAA catabolic circuitry in heart. Genetic inactivation of BCAA catabolic pathway resulted in elevated cardiac BCKA levels and promoted cardiac dysfunction in response to mechanical overload, associated with increased oxidative stress and impaired mitochondrial respiration. Taken together, our data established for the first time that BCAA catabolic reprogramming is an integral component of metabolic remodeling that contributes to heart failure progression.

Abstract 86: Catabolic Remodeling of Branched Chain Amino Acids in Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Haipeng Sun ◽  
Meiyi Zhou ◽  
Chen Gao ◽  
Kristine Olson ◽  
Ji-Youn Youn ◽  
...  
Keyword(s):  
Heart Failure ◽  
Amino Acids ◽  
Regulatory Protein ◽  
Pressure Overload ◽  
Branched Chain Amino Acids ◽  
Atp Production ◽  
Genetic Ablation ◽  
Catabolic Genes ◽  
Metabolic Remodeling ◽  
Branched Chain

Metabolic remodeling is an integral part of heart failure. Although glucose and fatty acids metabolism have been extensively studied, little is known about the role of amino acids homeostasis in heart physiology and pathology. Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids for both protein synthesis and cellular signaling. Elevated levels of BCAAs have been linked with heart failure. However, the underlying regulatory mechanism and functional significance of abnormal BCAA catabolism in heart failure have not been established. We found that genes involved in BCAA catabolism, including a key regulatory protein PP2Cm, are significantly down-regulated at mRNA as well as protein level in pressure-overload induced failing heart in mice. Furthermore, the concentrations of BCAA catabolic products branched-chain keto acids (BCKAs) are also elevated in heart tissues of post TAC mice. Interestingly, the down-regulation of BCAA catabolic genes mimics a similar expression pattern observed in fetal heart, suggesting that decreased BCAA catabolic activity is part of the metabolic remodeling in pathologically stressed heart from an adult to a fetal-like state. Genetic ablation of PP2Cm in mouse leads to defect in BCAA catabolism and accumulation of BCAAs and BCKAs in cardiac tissue and serum. PP2Cm deficient mice had lower cardiac contractility and higher susceptibility to develop heart failure under pressure overload. In addition, BCKAs treatment to isolated mitochondria resulted in lower oxygen consumption rate and ATP production. PP2Cm deficiency as well as BCKAs treatment induced oxidative stress in cardiomyocyte and antioxidant treatment ameliorated the development of heart failure in PP2Cm deficient animals. Together, these data indicated that BCAA catabolic remodeling is likely an integrated component of metabolic remodeling during heart failure. More importantly, mis-regulation of BCAA catabolism in heart promoted heart failure progression, involving direct impact on mitochondrial function and redox homeostasis in cardiomyocytes.

scholarly journals Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice

2019 ◽  
Author(s):  
Ivan Menendez-Montes ◽  
Beatriz Escobar ◽  
Beatriz Palacios ◽  
Manuel J. Gomez ◽  
Elena Bonzon ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heart Development ◽  
Cardiac Development ◽  
Building Blocks ◽  
Embryonic Heart ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Metabolic Switch ◽  
Cardiac Growth ◽  
Cardiac Progenitors

AbstractRationaleHypoxia is an important environmental cue implicated in several physiopathological processes, including heart development. Several mouse models of activation or inhibition of hypoxia have been previously described. While gain of function models have been extensively characterized and indicate that HIF1 signaling needs to be tightly regulated to ensure a proper cardiac development, there is lack of consensus in the field about the functional outcomes of HIF1α loss.ObjectiveIn this study, we aim to assess the consequences of cardiac deletion of HIF1α during heart development and identify the cardiac adaptations to HIF1 loss.Methods and ResultsHere, we used a conditional deletion model ofHif1ain NKX2.5+cardiac progenitors. By a combination of histology, electron microscopy, massive gene expression studies, proteomics, metabolomics and cardiac imaging, we found that HIF1α is dispensable for cardiac development.Hif1aloss results in glycolytic inhibition in the embryonic heart without affecting normal cardiac growth. However, together with a premature increase in mitochondrial number by E12.5, we found global upregulation of amino acid transport and catabolic processes. Interestingly, this amino acid catabolism activation is transient and does not preclude the normal cardiac metabolic switch towards fatty acid oxidation (FAO) after E14.5. Moreover,Hif1aloss is accompanied by an increase in ATF4, described as an important regulator of several amino acid transporters.ConclusionsOur data indicate that HIF1α is not required for normal cardiac development and suggest that additional mechanisms can compensateHif1aloss. Moreover, our results reveal the metabolic flexibility of the embryonic heart at early stages of development, showing the capacity of the myocardium to adapt its energy source to satisfy the energetic and building blocks demands to achieve normal cardiac growth and function. This metabolic reprograming might be relevant in the setting of adult cardiac failure.

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