Regulation of Energy Metabolism of the Heart during Acute Increase in Heart Work

Goodwin, Gary W.; Taylor, Christopher S.; Taegtmeyer, Heinrich

doi:10.1074/jbc.273.45.29530

Cited by 290 publications

(287 citation statements)

References 53 publications

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“…2C), even in the absence of an increase in arterial lactate concentration, which is similar to the relative increase we previously measure for oxidation of exogenous glucose and fatty acids in pigs subjected to a three-to fourfold increase in MV O 2 (20,26,36). Thus the heart increases its reliance on carbohydrate oxidation with increased cardiac work, as demonstrated in previous experimental studies in humans and pigs (16,30,36) and in the isolated perfused rat heart (12,17). Moreover, model simulations predicted a greater rate of lactate uptake and pyruvate oxidation as a function of increased arterial lactate concentration, which resulted in inhibition of fatty acid oxidation.…”

Section: Discussionsupporting

confidence: 86%

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

Zhou

Cabrera²,

Okere³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies. Am J Physiol Heart Circ Physiol 291: H1036-H1046, 2006. First published April 21, 2006 doi:10.1152/ajpheart.01382.2005.-In response to exercise, the heart increases its metabolic rate severalfold while maintaining energy species (e.g., ATP, ADP, and Pi) concentrations constant; however, the mechanisms that regulate this response are unclear. Limited experimental studies show that the classic regulatory species NADH and NAD ϩ are also maintained nearly constant with increased cardiac power generation, but current measurements lump the cytosol and mitochondria and do not provide dynamic information during the early phase of the transition from low to high work states. In the present study, we modified our previously published computational model of cardiac metabolism by incorporating parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and oxidative phosphorylation, and simulated the metabolic responses of the heart to an abrupt increase in energy expenditure. Model simulations showed that myocardial oxygen consumption, pyruvate oxidation, fatty acids oxidation, and ATP generation were all increased with increased energy expenditure, whereas ATP and ADP remained constant. Both cytosolic and mitochondrial NADH/NAD ϩ increased during the first minutes (by 40% and 20%, respectively) and returned to the resting values by 10 -15 min. Furthermore, model simulations showed that an altered substrate selection, induced by either elevated arterial lactate or diabetic conditions, affected cytosolic NADH/NAD ϩ but had minimal effects on the mitochondrial NADH/NAD ϩ , myocardial oxygen consumption, or ATP production. In conclusion, these results support the concept of parallel activation of metabolic processes generating reducing equivalents during an abrupt increase in cardiac energy expenditure and suggest there is a transient increase in the mitochondrial NADH/NAD ϩ ratio that is independent of substrate supply.diabetes; exercise; heart; lactate; mitochondria; modeling CARDIAC PUMP FUNCTION is fueled by ATP hydrolysis, which is precisely matched by ATP formation, primarily in the mitochondria (42). In the transition from rest to intense exercise, there is a three-to sixfold increase in the rate of cardiac power generation, myocardial oxygen consumption (MV O 2 ), and ATP turnover (25). Nevertheless, at high work states the myocardial ATP and ADP concentrations are maintained at a relatively constant level (2, 4, 36). There is rapid activation of NADH generation in the mitochondria, flux through the electron transport chain (ETC), and ATP production by oxidative phosphorylation to match exactly ATP breakdown in the cytosol. Studies in isolated mitochondria show that the generation of NADH from carbon substrates, oxygen consumption, and oxidative phosphorylation are turned on by feedback from an increase in ADP concentration (9); however, the regul...

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Section: Discussionsupporting

confidence: 86%

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

Zhou

Cabrera²,

Okere³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…20 However, several studies have suggested that increased glucose oxidation alone is insufficient for cardiac energy demands during stress. Total β-oxidation was increased by 40% when heart work was acutely increased, 21 and suppression of cardiac FA oxidation in peroxisome proliferator activated receptor (PPAR)-γ coactivator-1α knockout mice resulted in accelerated pressure-overload HF. 22 Augustus et al 23 reported that LPL knockout (hLpL0) hearts were susceptible to HF because of loss of LPL-mediated triglyceride lipolysis and low CPT-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Lipase Modulates Pressure Overload–Induced Heart Failure Through Alternative Pathway for Fatty Acid Uptake

et al. 2013

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A lthough a number of therapeutic advances have been made for the treatment of heart failure (HF), the prevalence and mortality of HF continue to grow worldwide. To develop novel therapies for HF, there is still a need to achieve better understanding of cardiac function and pathophysiology of HF using appropriate animal models of HF. The heart is constantly undergoing contraction and relaxation events that require a large amount of energy. Under physiological conditions, nearly 70% of the energy substrate used for myocardial contraction is derived from fatty acid (FA) oxidation, and the remainder comes from glucose and lactate oxidation.1 Exogenous FAs are obtained from free FAs that circulate in association with albumin and from the hydrolysis of triglyceride-rich lipoproteins via the actions of lipoprotein lipase (LPL). 2 The majority of FAs acquired by normal hearts are derived from esterified FAs contained in triglycerides and phospholipids. 3 Endothelial lipase (EL) is a member of the triglyceride lipase family. 4,5 EL is mainly expressed in vascular endothelial cells, but to a lesser extent, in macrophages, hepatocytes, and myocytes, 6 although the functional significance of EL expression in these cell types has not been fully understood. EL has primarily phospholipase activity and relatively less triglyceride lipase activity, and exhibits preferential substrate specificity for phospholipids on high-density lipoproteins (HDL). In other words, EL can release free FAs for energy source by hydrolyzing HDL phospholipids.7 Upregulation of EL is accompanied by secretion of both triglyceride lipase and phospholipase activities, 8 and can provide an alternative pathway for free FA uptake in adipose tissue when the action of LPL is absent.9 EL expression is detected in a variety of tissues, including heart, and EL expression in the heart was increased in animal models of septic shock and hypertension, 10,11 whereas the physiological role of EL in the heart remains unclear. Given its cardiac expression See Editorial Commentary, pp 955-957Abstract-Lipoprotein lipase has been considered as the only enzyme capable of generating lipid-derived fatty acids for cardiac energy. Endothelial lipase is another member of the triglyceride lipase family and hydrolyzes highdensity lipoproteins. Although endothelial lipase is expressed in the heart, its function remains unclear. We assessed the role of endothelial lipase in the genesis of heart failure. Pressure overload-induced cardiac hypertrophy was generated in endothelial lipase −/− and wild-type mice by ascending aortic banding. Endothelial lipase expression in cardiac tissues was markedly elevated in the early phase of cardiac hypertrophy in wild-type mice, whereas lipoprotein lipase expression was significantly reduced. Endothelial lipase −/− mice showed more severe systolic dysfunction with left-ventricular dilatation compared with wild-type mice in response to pressure overload. The expression of mitochondrial fatty acid oxidation-related genes, such as carnitine pa...

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“…This dichotomy may be due to the different features of the study groups. It is recognized as a dominance of fatty acid metabolism by the heart in the fasted state; when the heart is acutely stressed, it switches from fat to carbohydrates as fuel (25) because of a more convenient balance of oxygen consumption. In fact, artificial elevation of FFA in diabetic hearts reduces cardiac efficiency via an oxygen waste for noncontractile purposes (26).…”

Section: Effects Of Hemodynamic and Metabolic Variables On The Correlmentioning

confidence: 99%

Abnormal Left Ventricular Energy Metabolism in Obese Men With Preserved Systolic and Diastolic Functions Is Associated With Insulin Resistance

Perseghin

Ntali²,

Cobelli

et al. 2007

Diabetes Care

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OBJECTIVE -Perturbations in cardiac energy metabolism might represent early alterations in diabetes preceding functional and pathological changes. We evaluated left ventricular (LV) structure/geometry and function in relation to energy metabolism and cardiovascular risk factors in overweight/obese men using magnetic resonance techniques. RESULTS -LV mass increased across quartiles of BMI; meanwhile, the volumes did not differ. Parameters of LV systolic and diastolic function were not different among quartiles. The phosphocreatine-to-ATP ratio was reduced across increasing quartiles of mean Ϯ SD BMI (2.25 Ϯ 0.52, 1.89 Ϯ 0.26, 1.99 Ϯ 0.38, and 1.79 Ϯ 0.29; P Ͻ 0.006) in association with insulin sensitivity (computer homeostasis model assessment 2 model); this relation was independent of age, BMI, blood pressure, wall mass, HDL cholesterol, triglycerides, smoking habits, and metabolic syndrome. RESEARCH DESIGN AND METHODSCONCLUSIONS -Abnormal LV energy metabolism was detectable in obese men in the presence of normal function, supporting the hypothesis that metabolic remodeling in insulin resistant states precedes functional and structural/geometrical remodeling of the heart regardless of the onset of overt hyperglycemia. Diabetes Care 30:1520-1526, 2007C ardiovascular disease is the leading cause of death in patients with type 2 diabetes (1,2). The existence of a diabetic cardiomyopathy distinct from ischemic injury was confirmed, but the challenge of recognizing its specific features remained unresolved because diabetes could also provoke cardiac damage via coronary macrovascular disease, autonomic dysfunction, and coronary microvascular disease (3). It was proposed that altered metabolism and impaired insulin action in the heart might be cause and consequence of altered cardiac function (4) and that metabolic remodeling in diabetes might precede, cause, and sustain the functional and structural/geometrical remodeling of the heart (5). In keeping with this hypothesis, cardiac energy metabolism was found to be abnormal in patients with type 2 diabetes despite the lack of major cardiac dysfunctions (6) or the presence of diastolic dysfunction (7). Those studies were performed in middleage individuals (52-57 years old) in whom diabetes was diagnosed 1 (7) to 3 (6) years earlier. Therefore, the question whether the alterations of cardiac energy metabolism were due to the hyperglycemic state itself or whether they were secondary to the metabolic features characterizing the prediabetic state remained unanswered.This study was undertaken to assess whether obesity was associated with impaired cardiac structure/geometry, function, and energy metabolism and to establish whether these potential alterations were associated with the cardiovascular and metabolic risk factors accompanying insulin resistance conditions. RESEARCH DESIGN AND METHODSWe selected 81 apparently healthy men with no previous history of diabetes, hypertension, dyslipidemias, coronary, cerebral, or peripheral vascular events, no history of dilated cardiomy...

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Regulation of Energy Metabolism of the Heart during Acute Increase in Heart Work

Cited by 290 publications

References 53 publications

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

Endothelial Lipase Modulates Pressure Overload–Induced Heart Failure Through Alternative Pathway for Fatty Acid Uptake

Abnormal Left Ventricular Energy Metabolism in Obese Men With Preserved Systolic and Diastolic Functions Is Associated With Insulin Resistance

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