Cardiovascular Research Advance Access originally published online on May 31, 2008
Cardiovascular Research 2008 79(2):205-207; doi:10.1093/cvr/cvn134
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
Signalling in cardiac metabolism
Gary D. Lopaschuk1,* and
Daniel P. Kelly2
1 Cardiovascular Research Group, University of Alberta, 423 Heritage Medical Research Center, Edmonton, Alberta, Canada T6G 2S2
2 Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri, USA
* Corresponding author. Tel: +1 780 492 2170; fax: +1 780 492 9753. E-mail address: gary.lopaschuk{at}ualberta.ca
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1. Introduction
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The heart requires large amounts of energy to sustain contractile
function, and is the major consumer of energy in the body on
a weight basis. Energy reserves are limited in the heart, so
energy in the form of adenosine triphosphate (ATP) must be produced
continually by the catabolism of different energy carbon substrates.
The heart is an ‘omnivore’ and can use a number
of different energy substrates, including fatty acids, glucose,
lactate, pyruvate, ketones, and amino acids.
1–4 Myocardial
energy metabolism must be tightly regulated, as the heart cannot
afford to produce either too little or too much ATP. In the
normal healthy heart, almost all (>95%) of the ATP generated
in the heart comes from mitochondrial oxidative phosphorylation,
with the remainder being derived from glycolysis.
1–4 Of
these, fatty acids, glucose, and lactate normally make the greatest
contribution to overall energy metabolism, primarily because
the heart sees the highest concentration of these energy substrates.
Mitochondrial metabolism of fatty acids accounts for
60–90%
of the total energy production (in the form of ATP), with carbohydrates
contributing the remaining 10–40%.
3 The contribution of
fatty acids and carbohydrates to oxidative ATP production in
the heart is influenced by a number of conditions, including
alterations in hormonal control, workload, energy substrate
supply, and oxygen supply to the heart. The control of these
energy-producing pathways is complex, but the different pathways
normally work in perfect harmony to ensure the energy needs
of the myocardium are met. The energy homeostasis mechanisms
of the heart maintain constant ATP production despite periods
of dramatic shifts in workload to the heart, and changes in
energy substrate and/or oxygen supply to the heart. A complex
and integrated cardiac signalling pathway has evolved to allow
a precise match between cardiac energy production and usage.
This Spotlight issue of
Cardiovascular Research addresses some
of the complex signalling pathways involved in the physiological
control of energy metabolism in the heart. Dysregulation of
cardiac metabolic pathways relevant to common diseases that
leads to heart failure is also addressed.
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2. Control of myocardial mitochondrial function
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As mentioned, mitochondrial oxidative metabolism is the major
source of ATP production in the heart. It is now well established
that alterations in mitochondrial function contribute to the
pathogenesis of heart failure, including ischaemic heart disease,
diabetic cardiac dysfunction, hypertensive cardiac hypertrophy,
and various cardiomyopathies.
5 Considerable research interest
has focused on the complex processes controlling cardiac myocyte
mitochondrial biogenesis, including the key role of transcription
factors such as peroxisomal proliferator activated receptors
(PPAR)
and β, oestrogen-related receptors and upstream
regulators, and PPAR
co-activator (PGC-1
).
5 In this issue of
Cardiovascular Research, Ventura-Clapier
et al.6 review the
role of PGC-1
in the regulation of cardiac mitochondrial biogenesis.
Under normal conditions and in disease states, the authors discuss
how down-regulation of PGC-1
expression is linked to mitochondrial
dysfunction in heart failure. These studies are complemented
by the review of Samuels
et al.7 who address the genomic changes
in mitochondrial function that occur in heart failure as well
as other forms of heart disease. Samuels
et al. address the
molecular genetics, transcriptomics, and metabolomics of cardiac
metabolism, providing key translational insights into the potential
interaction between genomic variation and complex alterations
in mitochondrial and cardiac metabolism relevant to cardiac
pathological conditions.
While transcriptional control of mitochondrial function can occur in many pathological conditions, the review of Bray and Young8 demonstrates that many changes in metabolic gene expression occur in a diurnal manner. These authors review the exciting new advances in the area of cardiac function and circadian rhythm, including physiological and pathophysiological implications of diurnal alterations in cardiac metabolism. The impact of external signals on circadian rhythm on maladaptive changes in cardiac metabolism is also discussed.
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3. Control of glycolysis
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While glycolysis only provides 5–10% of the overall ATP
requirements for the normal heart under normal conditions, it
has been proposed that glycolysis serves to control membrane
ion flux.
9 During myocardial ischaemia, heart failure, and cardiac
hypertrophy, the contribution of glycolysis to ATP production
increases.
10 The control of glycolysis is complex, and, like
mitochondrial oxidative metabolism, relies on alterations in
hormonal control, allosteric control, phosphorylation control,
and transcriptional control. An important first step in the
uptake of glucose is the transport of insulin through glucose
transporters, primarily GLUT1 and GLUT4, the latter being highly
responsive to insulin. The molecular signalling pathways that
control insulin-stimulated glucose uptake have been the focus
of a considerable amount of research in the last decade. The
paper of Bertrand
et al.11 nicely reviews these molecular processes,
including the critical role of the phosphatidylinositol 3-kinase
(PI-3K) system and the Akt/PKB pathway. The paper also addresses
derangements in myocardial insulin signalling relevant to diabetes
and insulin resistance. Potential therapeutic options to improve
insulin signalling are also addressed.
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4. Signalling control of cardiac fatty acid metabolism
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Fatty acids are normally the primary source of carbon substrate
for the heart and originate either from free fatty acids bound
to albumin in the blood or from triacylglycerol present in lipoproteins.
4 The rates of fatty acid metabolism are controlled by the supply
of fatty acids, the degree of expression of key metabolic proteins
(enzymes and transporters)
6, and the complex regulatory pathways
including both allosteric regulation of enzymes and substrate–product
relationships.
1–4 In this issue of
Cardiovascular Research,
Schwenk
et al.12 describe the key role of CD36 in controlling
myocyte fatty acid uptake. This review also addresses the interplay
between insulin and AMP-activated protein kinase (AMPK) in controlling
these pathways. The authors raise the intriguing possibility
that in addition to its key role in regulating glucose uptake,
insulin may also serve a key role in regulating fatty acid uptake
via CD36 translocation. They also discuss the role of alterations
in CD36 translocation in mediating diabetes-induced changes
in fatty acid uptake.
Once transported across the sarcolemma, fatty acids are subsequently activated by esterification to fatty acyl-CoA by fatty acyl-CoA synthetase. Acyl CoA moieties can either be esterified to intracellular lipids or converted to long-chain fatty acylcarnitine by carnitine palmitoyltransferase I (CPT-I). An important regulator of myocyte fatty acid uptake and oxidation is malonyl-CoA, a potent endogenous inhibitor of CPT-I.13 Thus, malonyl-CoA decreases the uptake of fatty acids into the mitochondria, thereby reducing mitochondrial fatty acid β-oxidation. The importance of malonyl-CoA control in regulating fatty acid oxidation rates as well as the control of malonyl-CoA by a troika of enzymes—AMPK, acetyl-CoA carboxylase, and malonyl-CoA decarboxylase—is discussed in the review by Ussher and Lopaschuk.14 The possibility of targeting these enzymes to treat various cardiac pathologies is also discussed.
Once fatty acids are taken up into the mitochondria, they subsequently undergo oxidation by a number of β-oxidative enzymes. The activity of the β-oxidative enzymes is highly regulated by both allosteric control and gene transcriptional control of their expression. Indeed, many of the enzymes of fatty acid β-oxidation are controlled by PGC-1, PPAR, and PPARβ.5,6 Genomic analyses in various cardiac pathologies have demonstrated the importance of transcriptional control in determining the levels of these fatty acid oxidative enzymes. The original paper of Rennison et al.15 shows how the activity of the enzymes catalyzing the initial step of fatty acid β-oxidation, the acyl-CoA dehydrogenases, is decreased in heart failure. They also show, however, that the activity of acyl-CoA dehydrogenase can be increased with high-fat feeding, resulting in an improved mitochondrial function. At present, the importance of depressed mitochondrial fatty acid β-oxidation in heart failure as well as whether therapeutic approaches to treat heart failure should increase or decrease fatty acid oxidation are topics of substantial research interest.
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5. Exogenous hormonal and substrate control of cardiac energy metabolism
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Considerable recent interest has focused on how exogenous energy
substrate supply to the heart can contribute to cardiac pathology.
Exposure of the heart to high levels of fatty acids can result
in the accumulation of fatty acid intermediates within the heart
that can have deleterious effects on the heart.
16 The mechanisms
responsible for this ‘lipotoxicity’ are not completely
understood, but are addressed in the review by Chess and Stanley.
17 These authors also address the issue of ‘glucotoxicity’,
where exposure of the heart to excess levels of glucose can
lead to deleterious products of glucose metabolism. The role
of diet in preventing heart failure from lipotoxicity and glucotoxicity
is also addressed in this review. The original article by Bermudez
et al.18 also examines how excess lipid supply to the heart
in the form of triacylglycerol can contribute to vascular dysfunction
by promoting lipid-mediated gene expression of genes involved
in cell proliferation and inflammation.
Hormones released from adipocytes (i.e. adipokines) have been shown to have significant actions on multiple organ systems, including the heart. This includes adipokines such as leptin and adiponectin. The role of adipokines on cardiac metabolic signalling pathways is discussed by Karmazyn et al.19 These authors also present a balanced view of how these adipokines can exert both salutary and deleterious effects on the heart. A better understanding of how these adipocyte signalling pathways function could identify some important therapeutic targets for treating heart diseases.
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6. Conclusions
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A plentiful and continuous production of energy is critical
for the maintenance of cardiac function. The signalling pathways
that ensure an adequate supply of energy to the heart are complex.
We now know that the control of myocardial fuel metabolism becomes
deranged in the diseased heart. Accordingly, it is important
to understand how these pathways function. We hope that the
articles in this Spotlight issue will provide improved understanding
of metabolic signalling pathways while providing a stimulus
for further research in this area. A better understanding of
these pathways should result in new therapeutic targets and
strategies aimed at optimizing energy metabolism in order to
prevent or treat heart failure.
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Notes
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The opinions expressed in this article are not necessarily those
of the Editors of
Cardiovascular Research or of the European
Society of Cardiology.
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References
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- Bing RJ, Siegel A, Ungar I, Gilbert M. Metabolism of the human heart. II. Studies on fat, ketone and amino acid metabolism. Am J Med (1954) 16:504–515.[CrossRef][Web of Science][Medline]
- Wisneski JA, Gertz EW, Neese RA, Mayr M. Myocardial metabolism of free fatty acids. Studies with 14C-labeled substrates in humans. J Clin Invest (1987) 79:359–366.[Web of Science][Medline]
- van der Vusse GJ, van Bilsen M, Glatz JF. Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res (2000) 45:279–293.[Abstract/Free Full Text]
- Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schönekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta (1994) 1213:263–276.[Medline]
- Finck BN, Kelly DP. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) regulatory cascade in cardiac physiology and disease. Circulation (2007) 115:2540–2548.[Free Full Text]
- Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1. Cardiovasc Res (2008) 79:208–217.[Abstract/Free Full Text]
- Samuels JL, Schaub MC, Zaugg M, Mamas M, Dunn WB, Swynghedauw B. Genomics in cardiac metabolism. Cardiovasc Res (2008) 79:218–227.[Abstract/Free Full Text]
- Bray MS, Young ME. Diurnal variations in myocardial metabolism. Cardiovasc Res (2008) 79:228–237.[Abstract/Free Full Text]
- Opie LH, Sack MN. Metabolic plasticity and the promotion of cardiac protection in ischemia and ischemic preconditioning. J Mol Cell Cardiol (2002) 34:1077–1089.[CrossRef][Web of Science][Medline]
- Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev (2005) 85:1093–1129.[Abstract/Free Full Text]
- Bertrand L, Horman S, Beauloye C, Vanoverschelde JL. Insulin signalling in the heart. Cardiovasc Res (2008) 79:238–248.[Abstract/Free Full Text]
- Schwenk RW, Luiken JJFP, Bonen A, Glatz JFC. Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease. Cardiovasc Res (2008) 79:249–258.[Abstract/Free Full Text]
- McGarry JD, Mills SE, Long CS, Foster DW. Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. Biochem J (1983) 214:21–28.[Web of Science][Medline]
- Ussher JR, Lopaschuk GD. The malonyl CoA axis as a potential target for treating ischaemic heart disease. Cardiovasc Res (2008) 79:259–268.[Abstract/Free Full Text]
- Rennison JH, McElfresh TA, Okere IC, Patel HV, Foster AB, Patel KK, et al. Enhanced acyl-CoA dehydrogenase activity is associated with improved mitochondrial and contractile function in heart failure. Cardiovasc Res (2008) 79:331–340.[Abstract/Free Full Text]
- Szczepaniak LS, Victor RG, Orci L, Unger RH. Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. Circ Res (2007) 101:759–767.[Abstract/Free Full Text]
- Chess DJ, Stanley WC. Role of diet and fuel overabundance in the development and progression of heart failure. Cardiovasc Res (2008) 79:269–278.[Abstract/Free Full Text]
- Bermúdez B, López S, Pacheco YM, Villar J, Muriana FJG, Hoheisel JD, et al. Influence of postprandial triglyceride-rich lipoproteins on lipid-mediated gene expression in smooth muscle cells of the human coronary artery. Cardiovasc Res (2008) 79:294–303.[Abstract/Free Full Text]
- Karmazyn M, Purdham DM, Rajapurohitam V, Zeidan A. Signalling mechanisms underlying the metabolic and other effects of adipokines on the heart. Cardiovasc Res (2008) 79:279–286.[Abstract/Free Full Text]
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1. Introduction
2. Control of myocardial...