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Cardiovascular Research 2000 45(3):538-548; doi:10.1016/S0008-6363(99)00266-7
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Copyright © 2000, European Society of Cardiology

Metabolic aspects of programmed cell survival and cell death in the heart

Christophe Depre and Heinrich Taegtmeyer*

Division of Cardiology, University of Texas Houston Medical School, Houston, TX, USA

* Corresponding author. Fax: +1-713-500-6556 ht{at}heart.med.uth.tmc.edu

Received 22 June 1999; accepted 20 August 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Fuel selection, contractile...
 3 Challenging cell survival:...
 4 Programs of cardiac...
 5 Transition from cell...
 6 Cell death in...
 References
 
Normal cardiac function requires a tight interaction between metabolism, contractile function and gene expression. The main perturbation challenging this equilibrium in vivo is ischemia, which alters energy flux through the control of key enzymes. The review highlights metabolic imprints and energetic aspects of programmed cell survival, programmed cell death, and of necrosis. When sustained and severe, ischemia leads to a total collapse of energy transfer, to the accumulation of metabolic endproducts, and to the development of myocardial necrosis. When moderate, ischemia results in a coordinated cellular response including enhanced anaerobic glucose metabolism, a modification of cardiac gene expression, and the development of specific mechanisms for programmed cell survival (preconditioning, stunning, hibernation). Repetitive stress results in a decrease of contractile function, a downregulation of gene expression and an impairment of energy transfer, which eventually cause the heart to fail. When the failing heart becomes energy-depleted, the programs of cell survival are no longer operational and programmed cell death ensues. To define the point of departure from programmed cell survival to cell death remains a major challenge.

KEYWORDS Apoptosis; Energy metabolism; Gene expression; Heart failure; Hibernation; Stunning


   1 Introduction
Top
 Abstract
 1 Introduction
2 Fuel selection, contractile...
 3 Challenging cell survival:...
 4 Programs of cardiac...
 5 Transition from cell...
 6 Cell death in...
 References
 
Since the discovery that the mammalian heart receives its nutrients through the coronary circulation [1], the tight coupling of coronary flow, myocardial oxygen consumption and contractile performance is one of the fundamental principles of cardiovascular physiology. Cellular responses to a decrease in coronary flow are both immediate and sustained. Immediate responses are those affecting the transfer of energy from substrates to ATP and entail the activation or inactivation of highly regulated enzymes. Sustained responses involve adaptive changes in gene expression. The review highlights metabolic imprints and energetic aspects of programmed cell survival, programmed cell death, and of necrosis.

Energy metabolism is linked to both gene expression and enzyme regulation, as well as to contractile function. There is a clear interdependence of metabolism, contractile function and gene expression, through specific signals, sensors, transducers and effectors. The most common disturbance challenging this dynamic equilibrium is myocardial ischemia. The heart may develop specific responses which improve its resistance to ischemia, and these are commonly referred to as preconditioning, stunning and hibernation. In spite of their different characteristics, all adaptive processes are ultimately processes of ‘programmed cell survival.’ Common feature of programmed cell survival is an intact, functioning nucleus in the cardiac myocyte. The term of of ‘programmed cell survival’ contrasts the well-known phenomenon of programmed cell death and apoptosis [2,3], which occurs in the maladapted, failing heart [4].


   2 Fuel selection, contractile function and gene expression
Top
 Abstract
 1 Introduction
 2 Fuel selection, contractile...
3 Challenging cell survival:...
 4 Programs of cardiac...
 5 Transition from cell...
 6 Cell death in...
 References
 
The wide range of environmental changes to which heart muscle is able to respond require an adaptation of energy transfer mechanisms (Fig. 1). Energy reserves in heart muscle are insufficient to sustain contractile function in the absence of a continuous flux of energy from oxidizable substrates (Fig. 1). At an ATP content of about 20 µmol/g dry weight [5], and at a myocardial O2 consumption rate of 5 mmol/h per gram dry weight [6], the heart turns over its entire ATP pool every 4–5 s. Although phosphocreatine (about 30 µmol/g dry weight) through the creatine kinase reaction, and ADP through the adenylate kinase reaction buffer ATP, the energy reserve in the absence of oxidizable substrates is still very limited. The heart therefore relies on the continuous supply and metabolism of energy providing substrates. Most of its energy requirements are met by the oxidation of exogenous substrates (fatty acids, glucose, lactate and ketone bodies). Glycogen may be preferentially oxidized during stress [7]. The contribution of each substrate to the fuel for respiration depends on several parameters, which will now be discussed.


Figure 1
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  		Fig. 1 Energy transfer in heart muscle: the steps are divided into metabolism of energy-providing substrates, combustion of substrates coupled to ATP production (oxidation), and ATP hydrolysis by contractile proteins and ion pumps (utilization). The high rate of energy turnover requires ATP stores to be continuously replenished by oxidative phosphorylation of ADP. Ischemia induces coordinated adaptive responses to decreased oxygen tension. Severe ischemia results, however, in a collapse of the entire system and the accumulation of metabolic endproducts (see text for details).

 
Quantity and quality of substrate supply to the heart are determined by the dietary state and physical activity of the body. Long chain fatty acids are the major substrates for the heart (Fig. 1). With fasting, fatty acids and triglycerides are released from the adipose tissue, and enter the circulation. Fatty acids are taken up by the cardiac cell to be degraded to acetyl-CoA (Fig. 1). Oxidation of acetyl-CoA begins with the formation of citrate, which is the first intermediate of the citric acid cycle (Fig. 1). By an allosteric feed-back mechanism, citrate inhibits glucose utilization [8,9]. Glucose becomes the main substrate for oxidative metabolism of the heart when fatty acid levels are low and when the concentrations of glucose and insulin are high, as in the post-prandial state. Glucose decreases rates of long-chain fatty acids oxidation [6], most likely by preventing the uptake of fatty acids by the mitochondria [10,11]. Other substrates are lactate and ketone bodies. Lactate contributes significantly to the supply of carbons for the tricarboxylate cycle and may replace all other substrates (including glucose), especially after exercise [12]. Ketone bodies are produced from the catabolism of fatty acids in the liver, and their plasma concentration rises mainly with starvation, during pregnancy, and in diabetic ketoacidosis [13]. Both lactate and ketone bodies inhibit glycolytic flux, by the same mechanism as fatty acids [14,15]. This inhibition is relieved by adrenergic stimulation [15]. Energy utilization is tightly coupled to contractile function (Fig. 1). Increased external work in working heart models increases glucose uptake [16,17] through recruitment of glucose transporters to the plasma membrane [18,19]. The positive inotropic action of epinephrine results not only in increased heart work, but also in a marked acceleration of glucose uptake and oxidation [15,20].

Energy supply and contractile function both affect cardiac gene expression [21]. For instance, the metabolic disturbances induced by diabetes (decreased glucose utilization and higher reliance upon fatty acids) [9,22] are accompanied by a change in myocardial transcription (decreased expression of glucose transporters, isoform switching of contractile proteins) [23,24] and an alteration in contractile function [25,26]. Similarly, changes in cardiac workload are followed by a response of genes coding for contractile proteins, ion pumps and metabolic enzymes [27–30]. This concerted genomic adaptation is often referred as the ‘fetal gene program’. The expression of a fetal gene program represents the adaptation of a specific set of genes to different energetic conditions. By adapting the expression of genes involved in energy supply and consumption, the myocardium adopts a profile of ‘energy sparing’ rather than ‘contractile efficiency’, as it is the case in the fetal heart [31]. Although changes in loading condition induce a regression of the myocardial gene pattern from the adult to the neonatal state, they do not alter the expression of genes responsible for cell determination, morphogenesis and exit from the cell cycle. The expression of a ‘fetal gene program’ is purely adaptive and does not imply per se irreversible cell damage, necrosis, oncosis or apoptosis.


   3 Challenging cell survival: metabolic consequences of myocardial ischemia
Top
 Abstract
 1 Introduction
 2 Fuel selection, contractile...
 3 Challenging cell survival:...
4 Programs of cardiac...
 5 Transition from cell...
 6 Cell death in...
 References
 
Hypoxia and ischemia–reperfusion may both induce apoptosis [32–36]. Under anaerobic conditions energy production relies on the mobilization of glycogen and anaerobic glycolysis which, however, amounts to no more than 5% of the energy derived from oxidative metabolism of glucose. Fatty acid oxidation ceases altogether. Adenosine is released, which promotes glucose uptake [37], but results in an irreversible loss of purine nucleotides. The combined effects of ATP hydrolysis and lactate production result in intracellular acidosis, accumulation of protons, inorganic phosphate, sodium, and calcium. The accumulation of inorganic phosphate and of protons has been implicated as a causal link to decreased contractile performance [38,39], whereas the accumulation of calcium in mitochondria and cytosol has been implicated as a causal link to irreversible cell damage [40,41]. Energy derived from glycolysis may be essential for the support of ion pumps and maintenance of cellular integrity. Indeed, physiological modulators of stress responses, including glycogen, may improve ischemia tolerance in vitro [42–44]. However, sustained and severe ischemia inevitably leads to cell death and necrosis.

The myocardial response to ischemia is regulated [45] to protect the structural and functional integrity of the cardiac myocyte [46]. Ischemia tampers myocardial energy metabolism by slowing aerobic metabolism and by accelerating anaerobic metabolism — a reversal of the well known Pasteur effect [47]. Glucose assumes a central role for energy production in the ischemic heart, when lack of oxygen induces a shift to anaerobic metabolism with rapid stimulation of glucose uptake, glycogenolysis and glycolytic flux [48]. The relative contribution of glucose to energy production is highly dependent on the severity of ischemia. Just as there is a continuum of the relative restriction of oxygen delivery, there is also a continuum of metabolic responses to ischemia [49–51]. As coronary flow decreases in vivo, there is an increase in the uptake of glucose and, paradoxically, also of fatty acids [52]. Enhanced myocardial glucose uptake and metabolism are controlled by the transmembrane glucose gradient [53], glucose transporters [54], rates of glucose phosphorylation [55], glycogen turnover [56], and by the reactions of the glycolytic pathway [57]. In moderate ischemia (reduction of coronary flow by 75%), glucose uptake and glycogen concentration remain unchanged, while glucose extraction increases and metabolism of glucose is directed from oxidation to lactate production [50]. In severe ischemia, myocardial glucose extraction is inversely related to coronary flow [58]. Therefore, glycogen breakdown is stimulated until the degree of ischemia becomes so severe that glycolysis is inhibited by the accumulation of its products [59]. The end of glycogen breakdown is concomitant with the end of anaerobic ATP production. There is a remarkably close correlation between glycogen content and ATP level in the ischemic myocardium (Fig. 2), as well as between glycogen and creatine phosphate concentration [42]. Once glycolysis and ATP production are inhibited, protons, sodium and calcium continue to accumulate [42,53,60]. This point corresponds to the onset of ischemic contracture, a phenomenon leading to post-ischemic dysfunction, irreversible ischemic damage, and cell death [61,62]. The decline of glucose uptake during prolonged, severe ischemia may be attenuated by interventions protecting the heart against ischemic injury, such as an increase of extracellular glucose concentration or the addition of insulin [53,63–66]. Paradoxically, intracellular acidosis attenuates the development of contracture in isolated cardiomyocytes [67,68] and also attenuates the degradation of adenine nucleotides [69].


Figure 2
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  		Fig. 2 ATP as a function of glycogen content in the heart: rabbit hearts were retrogradely perfused at constant flow with Krebs–Henseleit buffer containing 5 mM glucose as substrate. Ischemia was induced by reducing flow to 20% of baseline value. Hearts were freeze-clamped before ischemia or after 5–60 min of flow reduction. Each point represents an individual heart.

 
The increase in glucose uptake relative to coronary flow is termed ‘metabolism/perfusion mismatch’ [50,70]. ‘Metabolism/perfusion mismatch’ can either be the results of preserved metabolic activity with decreased flow, or the result of increased metabolic activity with preserved flow. Its long-term consequences are both metabolic and cellular. Chronic or repetitive ischemia results in the dedifferentiation of cardiac myocytes to a fetal phenotype [71] with enhanced glycogen deposition, which corresponds to preserved metabolic activity [72] and correlates linearly with the retention of [18F]2-glucose-2-deoxyglucose (FDG) [73].


   4 Programs of cardiac cell survival
Top
 Abstract
 1 Introduction
 2 Fuel selection, contractile...
 3 Challenging cell survival:...
 4 Programs of cardiac...
5 Transition from cell...
 6 Cell death in...
 References
 
The different phenomena of myocardial resistance to ischemia and cell death have been grouped in ischemic preconditioning, stunning and hibernation.

The observation that repeated 5-min coronary artery occlusions and reperfusions reduce the infarct size after a subsequent long period of occlusion in the dog [74] defined the general concept of ischemic preconditioning, meaning that protection against prolonged severe ischemia can be conferred by one or more preceding brief ischemic episodes. The search for the mechanism of preconditioning has triggered an almost unprecendented amount of investigations in the area of receptor activation and signal transduction. An early important finding was that a 5-min perfusion of adenosine was as protective as a 5-min coronary occlusion [75]. By increasing phospholipase C activity through its liaison to the extracellular A1 receptor, adenosine activates protein kinase C, the next key step in the transduction of preconditioning. A link between the receptor cascade and any metabolic correlate has not yet been established. In the dog, preconditioning has been shown to decrease glycogen breakdown, and to decrease the accumulation of glycolytic metabolites [76]. However, increasing myocardial glycogen levels before ischemia may have the same effects as preconditioning [44]. The decline of ATP and of creatine phosphate, and the development of intracellular acidosis are slower in preconditioned hearts than in controls [77]. Paradoxically, preconditioned hearts develop a more severe degree of ischemic contracture [78]. Preconditioning also alters the balance between BclXL and Bax, in favour of the anti-apoptotic effectors [79]. Therefore, the extent of apoptosis at reperfusion is reduced after ischemic preconditioning [80].

Myocardial stunning is defined as a postischemic contractile dysfunction despite restoration of flow and the absence of irreversible damage [81,82]. Dysfunction in stunned myocardium is followed by complete functional recovery. Mostly studied in animal models, stunning also occurs in patients. Examples are reversible contractile dysfunction after hypothermic ischemic arrest for cardiac surgery, after thrombolysis for acute myocardial infarction, after an episode of unstable angina, or even after a bicycle stress test [83,84]. The temporal sequence of stunning begins with the ischemia-induced increase of free intracellular calcium, inducing a desensitization and partial proteolysis of myofilaments by calcium-dependent proteases [85]. Another determinant of post-ischemic dysfunction is the generation of oxygen-derived free radicals at reperfusion [86], which inhibit different ionic pumps [87,88], induce a mitochondrial calcium release [89], and block glycolytic flux [90].

Hibernating myocardium represents a chronically dysfunctional myocardium most likely submitted to repetitive episodes of ischemia but still capable of improving contractile function after reperfusion [91]. The myocardium adapts the ventricular performance to the reduction of oxygen delivery, to prevent irreversible tissue damage. Indirect evidences support a deregulation of glycogen metabolism in hibernating heart, and several groups of investigators have reported that glycogen content in this tissue is dramatically increased [71,92,93]. Hibernating myocardium is detected at positron emission tomography by an increased signal from FDG [94], suggesting enhanced glucose uptake and glycogen accumulation in the same regions [73]. It is reasonable to assume that FDG, like 2-deoxyglucose, is incorporated into glycogen [95]. In human hibernating myocardium, a positive correlation exists between increased FDG uptake and glycogen accumulation [73]. Thus, the increased FDG signal in hibernating myocardium could be related to a stimulation of glucose uptake for glycogen synthesis, although this remains to be demonstrated directly. Interestingly, the accumulation of glycogen and other morphological alterations seen in hibernating tissue are also characteristic of the unloaded myocardium and of the fetal heart [96,97], suggesting that hibernation may induce a reliance on glucose for energy provision, similar to that observed in fetal heart.

What do ischemic preconditioning, myocardial stunning and hibernation have in common? Although the mechanisms are still not precisely defined [84], each of the three phenomena trigger specific tissue responses to ischemia and reperfusion. In principle these syndromes may occur in any tissue. Ischemia, or the cellular response to decreased blood flow, is more than a simple imbalance between supply and demand. The preconditioned heart efficiently improves its resistance to irreversible damage, even when oxygen and substrate supply are severely reduced. This resistance implies decreased utilization of endogenous substrate (like glycogen) and decreased accumulation of metabolic end-products (such as lactate). The hibernating myocardium has successfully adapted to a decrease in supply without evidence of a switch to anaerobic metabolism. The stunned myocardium enjoys a normal blood supply, although contraction is reduced while the myocyte repairs itself. In other words, while myocardial ischemia is associated with contractile dysfunction, contractile dysfunction can be present in the absence of ischemia and, like in diabetes, in the midst of plenty with respect to substrate supply and oxygen.

Understanding ischemia and reperfusion is also the clue to understanding stunning, hibernation and ischemic preconditioning. The functional recovery at reperfusion is mainly determined by the extent of irreversible ischemic damage. After brief episodes of ischemia (up to 20–30 min), oxidative metabolism rapidly returns, well before contractile activity is restored [98–101]. Stimulation of glucose oxidation at the onset of reperfusion improves and accelerates functional recovery, whereas inhibition of glucose utilization induces a strong impairment of post-ischemic contractile function [102–104]. When glycolysis is stimulated in reperfused myocardium, the cytosolic accumulation of calcium decreases [103]. Because pharmacologic interventions that prevent calcium accumulation in reperfused myocardium also decrease the severity of stunning [105], it is reasonable to assume that ATP produced from glycolysis is used preferentially to support the activity of ion pumps. The efficiency of this ionic homeostasis is further improved by stimulating the pyruvate dehydrogenase complex (PDC) [106], which should reduce the accumulation of protons brought on by glycolysis during ischemia. The breakdown of ATP produced from glycolysis induces a net production of protons which are consumed by pyruvate dehydrogenase and creatine kinase. When glycolysis is uncoupled from glucose oxidation, the resulting accumulation of protons stimulate the Na+–H+ exchanger at reperfusion [107]. As a result of the accumulation of Na+, the Na+–Ca2+ exchanger is stimulated, eventually leading to Ca2+ overload and reperfusion injury [108]. It has been suggested that, by activating pyruvate dehydrogenase, such accumulation can be limited and functional recovery may be improved [109].


   5 Transition from cell survival to cell death
Top
 Abstract
 1 Introduction
 2 Fuel selection, contractile...
 3 Challenging cell survival:...
 4 Programs of cardiac...
 5 Transition from cell...
6 Cell death in...
 References
 
When adaptative mechanisms of cardiac survival can no longer sustain cellular homeostasis, the disturbance of energy metabolism, contractile function and gene expression can trigger programmed cell death. It is important to emphasize that the combination of these three parameters is necessary to induce cell death and severe dysfunction. For instance, both streptozotocin-treated or aorta-banded animals can survive a long time without patent signs of cell death and ventricular dysfunction, whereas the combination of streptozotocin-induced diabetes with banding-induced overload induces severe myocardial damage within a few weeks [110–112]. As mentioned in the first part of this review, metabolic disturbances induce an adaptation of contractile function, whereas increased workload induces an adaptation of metabolic pathways. However, a simultaneous dysfunction of both energy-producing and energy-consuming pathways precipitates the heart into maladapation, cell death and organ failure.

The transduction mechanisms which mediate this transition are still under investigation. No sudden change can be found to explain this transition from adaptation to maladaptation, which more probably results from a progressive drift of the cardiomyocyte from equilibrium [113]. The cardiomyocyte can activate both pro-apoptotic and anti-apoptotic pathways. Several laboratories have delineated a role for ‘stress-responsive’ mitogen-activated protein kinases (JunK and p38-MAPK) in the development of apoptosis [35,114,115]. Apoptosis results not only from the activation of these kinases [114,116], but also from the balance between the different forms of ‘stress-responsive’ kinases [116]. The exact mechanism by which these kinases promote apoptosis is unknown. Recent evidence suggests that JunK activation might occur downstream of caspase activation [117]. Several stimuli involved in programmed cell death, including reactive oxygen species [118] and tumor necrosis factor {alpha} (TNF{alpha}) [119], are efficient activators of these ‘stress-responsive’ kinases [120,121]. However, reactive oxygen species also activate the ERK-type of MAPkinases (p42 and p44), which protect against apoptosis by inducing the production of cyclooxygenase-2 [122]. In addition, ERKs have an anti-apoptotic effect by inhibiting caspase activation [123]. Another anti-apoptotic mechanism is the phosphatidylinositol-3-kinase (PI-3 kinase) pathway. A downstream effector of PI-3 kinase is protein kinase B (PKB or Akt), which, among other anti-apoptotic effects [124], phosphorylates the pro-apoptotic protein bad. Phospho-bad is trapped by the 14-3-3 proteins, which prevents its inhibitory interaction with the anti-apoptotic protein bcl-2 (Fig. 3). The bad/bcl-2 interaction is restored after dephosphorylation of bad by the Ca2+/calmodulin-activated phosphoprotein phosphatase calcineurin (PP2B). Activation of this protein phosphatase has been shown to promote heart failure [125,126]. However, increased free Ca2+ concentration in the cardiomyocyte is not necessarily pro-apoptotic, because the Ca2+/calmodulin-activated protein kinase kinase CaMKK [127] also phosphorylates and activates PKB [128]. In addition to its inhibitory effect on bad function, PKB/Akt also inhibits, by phosphorylation, the proteolytic activity of caspase-9 [129]. A balance therefore exists between protective, anti-apoptotic signals (which probably take part to the molecular basis of the ‘cell survival syndromes’ described above) and pro-apoptotic pathways (Fig. 3). Chronic or repetitive stress might lead to the progressive downregulation of the protective mechanisms and to the sustained activation of pathways which eventually induce apoptosis.


Figure 3
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  		Fig. 3 Importance of mitochondria in necrosis and apoptosis: severe hypoxia leads to ATP depletion and necrosis. Resistance of the heart to stress depends on the balance between pro-apoptotic and anti-apoptotic pathways. Important signaling pathways protecting from apoptosis are ERKs, PKB and CamKK. Calcineurin and JunK have pro-apoptotic potential. Stability of the mitochondrial membrane also depends on the balance between free bcl-2 (or bcl-XL) and bcl-2 (bcl-XL) combined to bad or bax. Depending on the conditions, nitric oxide (NO) has a pro-apoptotic, anti-apoptotic, or a ‘pro-necrotic’ effect (see text for details).

 
Several observations relate the onset of apoptosis to metabolic dysfunction. To begin with, a major determinant of the apoptosis cascade is mitochondrial destabilization (characterized by a loss of membrane potential, generation of reactive oxygen species and liberation of cytochrome c) [130–132]. Because mitochondria are the main site of cardiac ATP production, it is not surprising that apoptosis is related to ATP depletion (Fig. 3). Decreased ATP content promotes the transfer of the pro-apoptotic protein Bax to the mitochondria [133]. Insertion of bax in the mitochondrial membrane creates pores through which cytochrome c can be extruded to the cytosol (Fig. 3). In other cell types, activation of the apoptotic pathway is accompanied by an impairment of glucose uptake and downregulation of the anaerobic production of ATP [134,135]. Interestingly, overexpression of bcl-2 counteracts the onset of apoptosis in conditions of ATP depletion [136]. This protective effect is multifactorial, including an inhibition of bax-induced release of cytochrome c and and inhibition of APAF-1 (Fig. 3). Bcl-2 is now well established as an anti-apoptotic protector in cardiac cells [137]. It has been suggested that bcl-2 induces a state of ‘metabolic hibernation’, which improves cell resistance in stress conditions [138]. Because apoptosis requires energy, severe depletion of ATP is followed by necrosis rather than apoptosis (Fig. 3) [139,140]. As stressed above, cardiac apoptosis therefore results from ‘mild’ but repetitive, or prolonged episodes of stress (ischemia, stretch, overload), which progressively downregulate protective mechanisms and activate pro-apoptotic pathways. To define this point of departure from programmed cell survival to cell death remains a major challenge.


   6 Cell death in the failing heart
Top
 Abstract
 1 Introduction
 2 Fuel selection, contractile...
 3 Challenging cell survival:...
 4 Programs of cardiac...
 5 Transition from cell...
 6 Cell death in...
References
 
Heart failure is the final common presentation of all forms of heart diseases. It is a systemic disease which begins and ends with the heart. Mechanical dysfunction of the failing heart is due to many factors, including neurohumoral disturbance, accumulation of extracellular matrix, alteration of excitation–contraction coupling and a maladaptation of myocardial energetics [141]. The latter includes an alteration in the mechanisms of energy storage, and a decreased expression of contractile proteins, metabolic enzymes and ion pumps. The energy supply from fatty acids is reduced in the failing heart by the downregulation of enzymes controlling fatty acid oxidation [142,143]. There is a higher reliance upon glucose for energy production in the failing than in the non-failing heart, although the expression of both glucose transporters (GLUT) is downregulated [144]. The clinical importance of the impairment of substrate utilization in heart failure has been demonstrated by the functional improvement observed in patients treated with glucose, insulin and potassium [145–148]. Stimulation of glucose uptake in hypoxic cardiomyocytes also protects against apoptosis in vitro [149]. The effect cannot be reproduced with other oxidizable substrates, and the molecular mechanism is still unknown. Potential explanations include a stimulation of anaerobic production of ATP, an activation of the glucose-response element (GRE), and/or an interaction of glucose with the pro-apoptotic hypoxia-inducible factor 1{alpha} (HIF-1{alpha}).

An imbalance in the rate of nitric oxide (NO) production also participates to the metabolic alterations of the failing heart. Decreased activity of the endothelial isoform of NO synthase [150] switches cardiac metabolism to a higher glucose utilization [63,151], whereas increased activity of the inducible isoform of NO synthase inhibits mitochondrial creatine kinase [152,153], cytochrome c oxidase [154] and several enzymes of the tricarboxylic acid cycle [155]. These isoform-related differences of NO synthase on cardiac metabolism are due to a different rate of NO production (about 100-fold higher with the inducible isoform) [156] and a different subcellular localization [157]. The role of NO in cardiac apoptosis remains undefined. High rates of NO production can be anti-apoptotic through inhibition of caspase activity by nitrosylation, or pro-apoptotic by activation of poly(ADP-ribose)polymerase [158–160]. High rates of NO production are also ‘pro-necrotic’ through the formation of peroxynitrite, alteration of the mitochondrial permeability to Ca2+, and inhibition of the enzymes involved in ATP synthesis and transport [155,161–163].

Metabolic disturbance in the failing heart also includes an alteration of gene expression [142,164–169]. The changes of gene expression in the failing human heart mainly involve proteins regulating cardiac energetics, which are expressed in different isoforms. Contractile efficiency is reduced by the decreased expression of myosin heavy chain (MHC) [164]. Calcium handling is perturbed by the decreased expression of the sarcoendoplasmic Ca2+-ATPase (SERCA 2a) [170] and ion pumps of the sarcolemma.In addition to the decreased expression of the ‘adult’ isoforms (such as {alpha}MHC or GLUT4), which is an adaptation to overload, the failing heart also downregulates the expression of the corresponding ‘fetal’ isoforms (such as βMHC or GLUT1) [144]. This global downregulation of transcripts precipitates the heart in a state of energy starvation and irreversible contractile dysfunction. This drift from energetic homeostasis precipitates cardiac apoptosis [4,132], by making the failing heart even more vulnerable to pro-apoptotic conditions, such as hypoxia [33,34], ischemia [32,35], overload [171], myocardial infarction [172], as well as the production of TNF{alpha} [119,173], of reactive oxygen species [174] and of NO [175].

Recent data in the failing human heart from our laboratory show that unloading by left ventricular assist devices (LVAD) stimulates the reexpression of ‘fetal’ isoforms of these genes involved in myocardial energetics, and therefore reproduces the pattern of energy sparing described above for animal models. Together with a decrease of ventricular volume, this isoform-specific transcriptional reactivation by unloading may represent the molecular basis for the functional improvement of patients under LVAD treatment. In addition to this metabolic improvement, LVAD treatment also suppresses several stimuli of cardiac apoptosis, including a decrease in the cardiac production of TNF{alpha} and a downregulation of the expression of the inducible isoform of NO synthase. Interestingly, LVAD treatment also protects the failing heart against apoptosis by increasing the transcription of anti-apoptotic genes, such as Bcl-XL [176].

Time for primary review 14 days.


   References
Top
 Abstract
 1 Introduction
 2 Fuel selection, contractile...
 3 Challenging cell survival:...
 4 Programs of cardiac...
 5 Transition from cell...
 6 Cell death in...
 References
 

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