Malonyl-CoA metabolism in cardiac myocytes

Hamilton, Clayon B.; Ed, Saggerson

doi:10.1042/bj3500061

Cited by 35 publications

(36 citation statements)

References 36 publications

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“…However, the ratio of C18 to C16 fatty acids in the heart is twice that of plasma (10), purified cardiac myocytes were able to desaturate and elongate labeled linoleic acid (34), and there is no satisfactory explanation for the fate of considerable amounts of malonyl-CoA in the heart (21). In our NRVM cultures, we have detected significant mRNA expression and induction by FN of fatty acid synthetase (Fasn) and other genes in the fatty acid biosynthesis pathway.…”

Section: Fibronectin-induced Cardiomyocyte Hypertrophymentioning

confidence: 81%

“…Although the downregulation of fatty acid oxidation in cardiac hypertrophy has been extensively reported, the ability of cardiac myocytes to synthesize and elongate fatty acids has been poorly studied, since the heart is thought incapable of significant fatty acid synthesis (16,21). However, the ratio of C18 to C16 fatty acids in the heart is twice that of plasma (10), purified cardiac myocytes were able to desaturate and elongate labeled linoleic acid (34), and there is no satisfactory explanation for the fate of considerable amounts of malonyl-CoA in the heart (21).…”

Section: Fibronectin-induced Cardiomyocyte Hypertrophymentioning

confidence: 99%

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Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

Chen

Huang

Stewart

et al. 2004

Physiological Genomics

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(FN) is an extracellular matrix protein that binds to integrin receptors and couples cardiac myocytes to the basal lamina. Cardiac FN expression is elevated in models of pressure overload, and FN causes cultured cardiac myocytes to hypertrophy by a mechanism that has not been characterized in detail. In this study, we analyzed the gene expression changes induced by FN in purified rat neonatal ventricular myocytes using the Affymetrix RAE230A microarray, to understand how FN affects gene expression in cardiac myocytes and to separate the effects contributed by cardiac nonmyocytes in vivo. Pathway analysis using z-score statistics and comparison with a mouse model of cardiac hypertrophy revealed several pathways stimulated by FN in cardiac myocytes. In addition to the known cardiac myocyte hypertrophy markers, FN significantly induced metabolic pathways including virtually all of the enzymes of cholesterol biosynthesis, fatty acid biosynthesis, and the mitochondrial electron transport chain. FN also increased the expression of genes coding for ribosomal proteins, translation factors, and the ubiquitin-proteasome pathway. Interestingly, cardiac myocytes plated on FN showed elevated expression of the fibrosis-promoting peptides connective tissue growth factor (CTGF), WNT1 inducible signaling pathway protein 2 (WISP2), and secreted acidic cysteine-rich glycoprotein (SPARC). Our data complement in vivo studies and reveal several novel genes and pathways stimulated by FN, pointing to cardiac myocyte-specific mechanisms that lead to development of the hypertrophic phenotype. extracellular matrix; integrin; ventricular remodeling; signal transduction; gene expression profiling OUTSIDE-IN SIGNALING CHARACTERIZES the cellular effects mediated by interaction of cellular receptors with the extracellular matrix. In neonatal rat ventricular myocytes (NRVM), clustering of integrin receptors induced by fibronectin (FN) (39,40) or RGD peptides (3) elicits a hypertrophic response, characterized by a 1.5-to 3-fold increase in cellular area and corresponding increases in global mRNA and protein synthesis, together with enhanced myofibrillogenesis and sarcomeric assembly. FN also induces increased formation of focal adhesions and costameres, which are sites of contact of extracellular matrix with integrins and associated cytoskeletal proteins associated with the Z-disks of the sarcomere (39). As in other models of hypertrophy, the hypertrophic response is accompanied by changes in gene expression, with increased expression of the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and fetal isoforms of sarcomeric proteins such as ␤-myosin heavy chain (␤MHC) and ␣-skeletal actin (␣SkA).The pathophysiological relevance of the FN-induced, integrin-mediated pathway is highlighted by the observation of increased deposition of FN in the extracellular matrix in animal models of cardiac hypertrophy and in patients with cardiac failure (5,20,22,29,42,45). The increased synthesis of FN is in part mediated...

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Section: Fibronectin-induced Cardiomyocyte Hypertrophymentioning

confidence: 81%

Section: Fibronectin-induced Cardiomyocyte Hypertrophymentioning

confidence: 99%

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

Chen

Huang

Stewart

et al. 2004

Physiological Genomics

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“…3). Since malonyl-CoA exists in cytosol and mitochondria (18,22,47), it is possible that the cytosolic malonyl-CoA decreased, while mitochondrial malonyl-CoA increased. Malonyl-CoA inhibits CPT-I on the cytosolic side of the enzyme (22,44) and is produced in the cytosol and mitochondrial matrix from acetyl-CoA (44).…”

Section: Discussionmentioning

confidence: 99%

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Zhou¹,

Huang²,

Yuan³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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WC. Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation. Am J Physiol Heart Circ Physiol 294: H954-H960, 2008. First published December 14, 2007 doi:10.1152/ajpheart.00557.2007.-Inhibition of myocardial fatty acid oxidation can improve left ventricular (LV) mechanical efficiency by increasing LV power for a given rate of myocardial energy expenditure. This phenomenon has not been assessed at high workloads in nonischemic myocardium; therefore, we subjected in vivo pig hearts to a high workload for 5 min and assessed whether blocking mitochondrial fatty acid oxidation with the carnitine palmitoyltransferase-I inhibitor oxfenicine would improve LV mechanical efficiency. In addition, the cardiac content of malonyl-CoA (an endogenous inhibitor of carnitine palmitoyltransferase-I) and activity of acetyl-CoA carboxylase (which synthesizes malonyl-CoA) were assessed. Increased workload was induced by aortic constriction and dobutamine infusion, and LV efficiency was calculated from the LV pressure-volume loop and LV energy expenditure. In untreated pigs, the increase in LV power resulted in a 2.5-fold increase in fatty acid oxidation and cardiac malonyl-CoA content but did not affect the activation state of acetyl-CoA carboxylase. The activation state of the acetyl-CoA carboxylase inhibitory kinase AMP-activated protein kinase decreased by 40% with increased cardiac workload. Pretreatment with oxfenicine inhibited fatty acid oxidation by 75% and had no effect on cardiac energy expenditure but significantly increased LV power and LV efficiency (37 Ϯ 5% vs. 26 Ϯ 5%, P Ͻ 0.05) at high workload. In conclusion, 1) myocardial fatty acid oxidation increases with a short-term increase in cardiac workload, despite an increase in malonyl-CoA concentration, and 2) inhibition of fatty acid oxidation improves LV mechanical efficiency by increasing LV power without affecting cardiac energy expenditure.acetyl-CoA carboxylase; AMP-activated protein kinase; exercise; fatty acids; heart; mitochondria ONE OF THE MAJOR DETERMINANTS of myocardial oxygen consumption (MV O 2 ) at a given rate of left ventricular (LV) power generation is mitochondrial substrate selection (23, 44). Under normal resting conditions, fatty acid oxidation is the predominant source of energy for cardiac power generation (60 -80%); however, studies in humans (39), dogs (30, 31), and pigs (25) in vivo and in isolated perfused rat (3, 21) and mouse (20) hearts show that, with high rates fatty acid oxidation, the external power is reduced for a given MV O 2 (3,30,39). In the failing heart or during acute ischemia and/or reperfusion, pharmacological treatment with agents that inhibit myocardial fatty acid oxidation (5, 6) or directly activate carbohydrate oxidation (2, 28, 41) increases LV function without affecting MV O 2 and, therefore, improves LV mechanical efficiency (defined as the ratio of external LV power to LV energy expenditure). However, the effect of inhibition of fatty acid oxida...

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“…First, how can one explain that long-chain fatty acids (LCFA) are ␤-oxidized at an intracellular malonyl-CoA concentration that should inhibit completely the prevailing muscle isoform of carnitine palmitoyl transferase 1? Proposed explanations include malonylCoA protein binding and/or compartmentation (3,13,15,18,25). Second, how are cytosolic acetyl-CoA and malonyl-CoA levels correlated with fat and carbohydrate oxidation and the citric acid cycle (CAC) flux in mitochondria?…”

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confidence: 99%

Probing the link between citrate and malonyl-CoA in perfused rat hearts

Poirier¹,

Vincent²,

Reszko

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Little is known about the sources of cytosolic acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of fatty acid oxidation in the heart. We tested the hypothesis that citrate provides acetyl-CoA for malonyl-CoA synthesis after its mitochondrial efflux and cleavage by cytosolic ATP-citrate lyase. We expanded on a previous study where we characterized citrate release from perfused rat hearts (Vincent G, Comte B, Poirier M, and Des Rosiers C. Citrate release by perfused rat hearts: a window on mitochondrial cataplerosis. Am J Physiol Endocrinol Metab 278: E846-E856, 2000). In the present study, we show that citrate release rates, ranging from 6 to 22 nmol/min, can support a net increase in malonyl-CoA concentrations induced by changes in substrate supply, at most 0.7 nmol/min. In experiments with [U-13 C](lactate ϩ pyruvate) and [1-13 C]oleate, we show that the acetyl moiety of malonyl-CoA is derived from both pyruvate and long-chain fatty acids. This 13 Clabeling of malonyl-CoA occurred without any changes in its concentration. Hydroxycitrate, an inhibitor of ATP-citrate lyase, prevents increases in malonyl-CoA concentrations and decreases its labeling from [U-13 C](lactate ϩ pyruvate). Our data support at least a partial role of citrate in the transfer from the mitochondria to cytosol of acetyl units for malonylCoA synthesis. In addition, they provide a dynamic picture of malonyl-CoA metabolism: even when the malonyl-CoA concentration remains constant, there appears to be a constant need to supply acetyl-CoA from various carbon sources, both carbohydrates and lipids, for malonyl-CoA synthesis.gas chromatography-mass spectrometry; adenosine 5Ј-triphosphate-citrate lyase; hydroxycitrate; acetyl-coenzyme A; citric acid cycle; 13 C-substrate; isotopomer analysis THE INTRACELLULAR CONCENTRATION of malonyl-CoA modulates a number of physiological and pathophysiological events. These effects of malonyl-CoA are related to its inhibition of carnitine palmitoyl transferase 1. The latter controls the entry of long-chain acyl-CoA into mitochondria, where they are ␤-oxidized for energy production. In addition, carnitine palmitoyl transferase 1 activity affects cytosolic concentrations of longchain acyl-CoAs, which influence signal transduction and binding of nuclear transcription factors (5,16,19,42). In lipogenic tissues such as the liver, malonyl-CoA is both a modulator of fatty acid oxidation and an intermediate of fatty acid synthesis (25). In nonlipogenic tissues such as the heart and skeletal muscle, cytosolic malonyl-CoA modulates fatty acid oxidation and is a component of a fuel-sensing and signaling mechanism that responds to changes in the cell's substrate supply and energy expenditure (31, 33). Recently, a dysregulated malonyl-CoA metabolism has been implicated in insulin resistance (33), apoptosis (19), and functional recovery of the heart after ischemia (20). In the heart, the regulatory role of cytosolic malonylCoA is supported by the kinetic and regulatory properties of enzymes involved in its meta...

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Malonyl-CoA metabolism in cardiac myocytes

Cited by 35 publications

References 36 publications

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Probing the link between citrate and malonyl-CoA in perfused rat hearts

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