Cardiac fatty acid metabolism is preserved in the compensated hypertrophic rat heart

Degens, Hans; Brouwer, K. F. J. de; Gilde, Andries J.; Lindhout, M.J.; Willemsen, P. H. M.; Janssen, Ben J. A.; Vusse, Ger J.; Bilsen, Marc van

doi:10.1007/s00395-005-0549-0

Cited by 68 publications

(44 citation statements)

References 28 publications

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“…40, 41 In rats with compensated cardiac hypertrophy generated by abdominal aortic constriction, cardiac glycolysis was increased without glucose oxidation. 42 In a rat model of LV pressure overload, glucose oxidation was initially increased during the compensated phase of cardiac hypertrophy and then declined in the decompensated phase of HF. 14 In a murine model of LV pressure overload, glucose oxidation, glycolysis, and lactate oxidation were reduced at 6 weeks after the surgery.…”

Section: Metabolites Of Glycolysis and The Tca Cyclementioning

confidence: 99%

Metabolomic Analysis in Heart Failure

Ikegami

Shimizu

Yoshida

et al. 2018

Circ J

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10 s, resulting in the cycling of approximately 6 kg of ATP daily, and the heart displays metabolic flexibility to meet this extremely high demand for energy. 8 Under normal conditions, more than 95% of the ATP consumed in the heart is generated by oxidative phosphorylation, while glycolysis is responsible for approximately 5% and the tricarboxylic acid (TCA) cycle for the remainder. Metabolism of fatty acids generates 70-90% of the ATP required by the heart, with the rest being produced by oxidation of glucose, lactate, ketone bodies, and amino acids. 9 It is well known that utilization of fatty acids is reduced in the failing heart and there is a metabolic shift to generation of ATP from glucose. Such metabolic remodeling is considered to be reasonable because HF is associated with hypoxia and ATP generation per oxygen atom is more efficient when glucose is consumed, compared with fatty acids. 9 In patients with advanced HF, the heart is unable to utilize either metabolite and thus "runs out of fuel". 10 It is reported that the ATP level is approximately 30% lower in failing human hearts compared with non-failing hearts. 11 In addition to this classical premise about the metabolic profile of the failing heart, recent advances in the field of metabolomics have indicated that several metabolites and/or metabolic pathways have a role in HF, as described next. LipidsUnder physiological conditions, the heart mainly generates ATP from fatty acids, but this process declines with progression of HF. Under left ventricular (LV) pressure overload, excessive lipolysis occurs in visceral fat because of increased adrenergic signaling, and this leads to high circulating levels of free fatty acids (FFAs). 12 The serum I t is thought that at least 6,500 low-molecular-weight metabolites exist in humans, and these metabolites have various important roles in biological systems in addition to proteins and genes. 1 Comprehensive assessment of endogenous metabolites is called metabolomics, and recent advances in this field have enabled us to understand the critical role of previously unknown metabolites or metabolic pathways in the maintenance of homeostasis under both physiological and stress conditions. Techniques of metabolomic analysis have been elegantly reported and reviewed elsewhere, 2-4 so the details will not be repeated here. Instead, we will describe the metabolites/metabolic pathways that have been characterized using these techniques and analyzed to improve understanding of various physiological and pathological processes in the field of cardiology. In particular, we will focus on heart failure (HF) and how metabolomic analysis has contributed for improving our understanding of the pathogenesis of this critical condition. Cardiac MetabolismThe number of patients with HF continues to increase and this condition has become a major healthcare issue in many countries. Because the prognosis of severe HF is poor, there are many unmet medical needs for these patients, 5, 6 The pathogenesis of HF is complex and a simple approa...

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Section: Metabolites Of Glycolysis and The Tca Cyclementioning

confidence: 99%

Metabolomic Analysis in Heart Failure

Ikegami

Shimizu

Yoshida

et al. 2018

Circ J

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“…33 In addition, several studies have reported normal FA uptake, metabolism and carnitine palmitoyltransferase 1 activity, the rate limiting enzyme in mitochondrial beta-oxidation, in cardiac hypertrophy. 30,32 Our findings suggest that the cardiac hypertrophy caused by loss of Cav1 gene expression in cardiac fibroblasts was not severe enough to trigger a switch in myocardial energy metabolism commonly observed in pressure-or volume-overload induced hypertrophy and heart failure. Additional studies are needed to assess cardiac energy substrate utilization in decompensated and failing Cav1ko hearts.…”

Section: Discussionmentioning

confidence: 85%

“…29 However, recent studies by several groups argue that overt changes in cardiac energy metabolism may depend upon the degree of hypertrophy. [30][31][32] Miyamoto et al, measured the expression of several enzymes involved in FA metabolism and found that the levels of PPARα, a key transcriptional regulator of metabolic genes were normal in volume-overloaded hypertrophied rabbit hearts. 33 In addition, several studies have reported normal FA uptake, metabolism and carnitine palmitoyltransferase 1 activity, the rate limiting enzyme in mitochondrial beta-oxidation, in cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Hearts lacking caveolin-1 develop hypertrophy with normal cardiac substrate metabolism

et al. 2008

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Cell Cycle 7:16, 2509-2518 15 August 2008]; ©2008 Landes Bioscience Long-chain fatty acids (FA) are the primary energy source utilized by the adult heart. However, during pathological cardiac hypertrophy the fetal gene program is reactivated and glucose becomes the major fuel source metabolized by the heart. Herein we describe the metabolic phenotype associated with caveolin-1(Cav1) gene ablation (Cav1ko) in cardiac fibroblasts. Cav1, the primary protein component of caveolae in non-muscle cells co-localizes with a number of proteins involved in substrate metabolism, including, FA translocase (CD36) and the insulin receptor. We demonstrate that Cav1ko hearts develop cardiac hypertrophy and contractile dysfunction at 5-6mos of age. Surprisingly, we observed an increase in the uptake of Intralipid triglyceride and albumin bound FA by 25% and 47%, respectively, in Cav1ko hearts. Isolated perfused heart studies revealed no significant difference in glucose oxidation and glycolysis, however, we observed a trend toward increased FA oxidation in Cav1ko hearts. Real-time PCR analysis revealed no significant changes in the expression of genes involved in FA and glucose metabolism. We also report myocardial triglyceride, fatty acid and cholesterol levels are significantly reduced in Cav1ko hearts. Microarray gene expression analysis revealed changes in genes that regulate calcium ion and lipid transport as well as a number of genes not previously linked to cardiac hypertrophy. We observed a 4-fold increase in tetraspanin-2 gene expression, a transmembrane protein implicated in regulating intracellular trafficking. Oxysterol binding protein related protein-3, which has been implicated in intracellular lipid synthesis and transport, was increased 3.6-fold.In addition, sarcoplasmic reticulum Ca 2+ -ATPase 3, and calcyclin gene transcripts were significantly increased in Cav1ko hearts. In summary, targeted loss of Cav1 produces a unique model of cardiac hypertrophy with normal substrate utilization and expression of genes involved in energy metabolism.

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“…The expression of key genes known to regulate substrate metabolism was unchanged despite decreased left ventricular contractile function. Several studies suggest that the severity of pathological cardiac hypertrophy and heart failure dictates the metabolic switch toward glucose and away from FA as the primary fuel source (13). Our model of cardiac hypertrophy is unique in that the cardiomyopathy does not appear to result in altered cardiac substrate metabolism.…”

Section: Discussionmentioning

confidence: 95%

“…We previous reported the hyperactivation of ERK1/2 in Cav3KO hearts; however, the resulting increase in myocyte cell number and size did not alter myocardial energy metabolism in our model. Several recent studies suggest that overt changes in cardiac energy metabolism may depend upon the degree of hypertrophy (13). As compensatory hypertrophy progresses toward decompensated hypertrophy and eventually heart failure, changes in gene expression become more pronounced resulting in a shift away from FA as a fuel source (1).…”

Section: Discussionmentioning

confidence: 99%

Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts

Augustus¹,

Buchanan²,

Addya³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Augustus AS, Buchanan J, Addya S, Rengo G, Pestell RG, Fortina P, Koch WJ, Bensadoun A, Abel ED, Lisanti MP. Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts. Am J Physiol Heart Circ Physiol 295: H657-H666, 2008. First published June 13, 2008 doi:10.1152/ajpheart.00387.2008, the primary protein component of caveolae in muscle cells, regulates numerous signaling pathways including insulin receptor signaling and facilitates free fatty acid (FA) uptake by interacting with several FA transport proteins. We previously reported that Cav3 knockout mice (Cav3KO) develop cardiac hypertrophy with diminished contractile function; however, the effects of Cav3 gene ablation on cardiac substrate utilization are unknown. The present study revealed that the uptake and oxidation of FAs and glucose were normal in hypertrophic Cav3KO hearts. Real-time PCR analysis revealed normal expression of lipid metabolism genes including FA translocase (CD36) and carnitine palmitoyl transferase-1 in Cav3KO hearts. Interestingly, myocardial cAMP content was significantly increased by 42%; however, this had no effect on PKA activity in Cav3KO hearts. Microarray expression analysis revealed a marked increase in the expression of genes involved in receptor trafficking to the plasma membrane, including Rab4a and the expression of WD repeat/FYVE domain containing proteins. We observed a fourfold increase in the expression of cellular retinol binding protein-III and a 3.5-fold increase in 17␤-hydroxysteroid dehydrogenase type 11, a member of the short-chain dehydrogenase/ reductase family involved in the biosynthesis and inactivation of steroid hormones. In summary, a loss of Cav3 in the heart leads to cardiac hypertrophy with normal substrate utilization. Moreover, a loss of Cav3 mRNA altered the expression of several genes not previously linked to cardiac growth and function. Thus we have identified a number of new target genes associated with the pathogenesis of cardiac hypertrophy. cardiomyopathy; caveolae; fatty acids; isolated perfused hearts; adenosine 3Ј,5Ј-cyclic monophosphate FIRST DESCRIBED NEARLY sixty years ago, caveolae are 50-to 100-nm flask-shaped plasma membrane invaginations enriched in cholesterol, sphingolipids, and the primary protein component, caveolin. Caveolins and caveolae are involved in a number of diverse cellular processes including signal transduction, vesicular transport, and cholesterol metabolism. The caveolin gene family consists of three gene products including caveolin-1 and -2, which are coexpressed in several tissues including adipocytes, fibroblast, smooth muscle, and endothelial cells. Caveolin-3 (Cav3) is expressed in skeletal, smooth, and cardiac muscle and is involved in several myocyte-specific functions. During development, Cav3 expression increases threefold beginning at postnatal day 2 until day 90 in the rat heart (41). Cav3 associates with the T tubule system during development (40) and localizes to the sarcolemma in mature muscle fibers (43). Furthermore, Cav...

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Cardiac fatty acid metabolism is preserved in the compensated hypertrophic rat heart

Cited by 68 publications

References 28 publications

Metabolomic Analysis in Heart Failure

Metabolomic Analysis in Heart Failure

Hearts lacking caveolin-1 develop hypertrophy with normal cardiac substrate metabolism

Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts

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