Abstract
BackgroundAlterations in cardiac energy metabolism contribute to the development and severity of heart failure (HF). In severe HF, overall mitochondrial oxidative metabolism is significantly decreased resulting in a reduced energy reserve. However, despite the high prevalence of HF with preserved ejection fraction (HFpEF) in our society, it is not clear what changes in cardiac energy metabolism occur in HFpEF, and whether alterations in energy metabolism contribute to the development of contractile dysfunction.MethodsWe directly assessed overall energy metabolism during the development of HFpEF in Dahl salt-sensitive rats fed a high salt diet (HSD) for 3, 6 and 9 weeks.ResultsOver the course of 9 weeks, the HSD caused a progressive decrease in diastolic function (assessed by echocardiography assessment of E’/A’). This was accompanied by a progressive increase in cardiac glycolysis rates (assessed in isolated working hearts obtained at 3, 6, and 9 weeks of HSD). In contrast, the subsequent oxidation of pyruvate from glycolysis (glucose oxidation) was not altered, resulting in an uncoupling of glucose metabolism and a significant increase in proton production. Increased glucose transporter (GLUT)1 expression accompanied this elevation in glycolysis. Decreases in cardiac fatty acid oxidation and overall adenosine triphosphate (ATP) production rates were not observed in early HF, but both significantly decreased as HF progressed to HF with reduced EF (i.e. 9 weeks of HSD).ConclusionsOverall, we show that increased glycolysis is the earliest energy metabolic change that occurs during HFpEF development. The resultant increased proton production from uncoupling of glycolysis and glucose oxidation may contribute to the development of HFpEF.
Highlights
Alterations in cardiac energy metabolism contribute to the development and severity of heart failure (HF)
It was recently reported that overexpressing Acetyl Coenzyme A Carboxylase both prevented diastolic dysfunction and reduced cardiac fatty acid oxidation in mice treated with Angiotensin II (Choi et al 2016; Fig. 3 Effect of a high salt diet (HSD) on Dahl salt-sensitive rat heart glucose metabolic enzymes. a Representative western blots. b Glucose transporter 1 (GLUT1), (c) Glucose transporter 4 (GLUT4), (d) Phosphoglycerate mutase 1 (PGAM1), (e) Lactate dehydrogenase A (LDHA) expression, and (f) Hypoxia inducible factor 1α (HIF1α) protein expression was measured in hearts from Dahl salt-sensitive rats fed either a low salt diet, 0.3% NaCl (Control) or a HSD, 8% NaCl, for 3, 6, or 9 weeks. n = 4–9 * p < 0.05 compared to Control. ** p < 0.05 between compared groups
One possibility may be that the overall decrease in mitochondrial oxidative metabolism, results in a compensatory rise in glycolysis (Kato et al 2010; Beer et al 2002; Masoud et al 2014; Zhang et al 2013; Neubauer 2007)
Summary
Alterations in cardiac energy metabolism contribute to the development and severity of heart failure (HF). An abundance of evidence indicates that alterations in energy metabolism contribute to the severity of heart failure (Kato et al 2010; Degens et al 2006; Lei et al 2004; Conway et al 1991; Nascimben et al 1995; Tian et al 1996; Beer et al 2002; Neubauer et al 1999; Mori et al 2013) This includes a decrease in overall cardiac mitochondrial oxidative metabolism as the severity of Fillmore et al Molecular Medicine (2018) 24:3 the development of heart failure. ATP is utilized to both remove these protons and maintain sodium and calcium homeostasis which decreases cardiac efficiency and contributes to the decrease in cardiac function (Lopaschuk et al 2010)
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