The malonyl CoA axis as a potential target for treating ...

Review

The malonyl CoA axis as a potential target for treatingischaemic heart disease

John R. Ussher and Gary D. Lopaschuk*

Cardiovascular Research Group, Department of Pediatrics, University of Alberta, Edmonton, Canada

Received 23 January 2008; revised 11 May 2008; accepted 16 May 2008; online publish-ahead-of-print 22 May 2008

Time for primary review: 20 days

Cardiovascular disease is the leading cause of death and disability for people living in western societies,with ischaemic heart disease accounting for the majority of this health burden. The primary treatmentfor ischaemic heart disease consists of either improving blood and oxygen supply to the heart or redu-cing the heart’s oxygen demand. Unfortunately, despite recent advances with these approaches, ischae-mic heart disease still remains a major health problem. Therefore, the development of new treatmentstrategies is still required. One exciting new approach is to optimize cardiac energy metabolism, par-ticularly by decreasing the use of fatty acids as a fuel and by increasing the use of glucose as a fuel.This approach is beneficial in the setting of ischaemic heart disease, as it allows the heart toproduce energy more efficiently and it reduces the degree of acidosis associated with ischaemia/reper-fusion. Malonyl CoA is a potent endogenous inhibitor of cardiac fatty acid oxidation, secondary to inhi-biting carnitine palmitoyl transferase-I, the rate-limiting enzyme in the mitochondrial uptake of fattyacids. Malonyl CoA is synthesized in the heart by acetyl CoA carboxylase, which in turn is phosphorylatedand inhibited by 50AMP-activated protein kinase. The degradation of myocardial malonyl CoA occurs viamalonyl CoA decarboxylase (MCD). Previous studies have shown that inhibiting MCD will significantlyincrease cardiac malonyl CoA levels. This is associated with an increase in glucose oxidation, a decreasein acidosis, and an improvement in cardiac function and efficiency during and following ischaemia.Hence, the malonyl CoA axis represents an exciting new target for the treatment of ischaemic heartdisease.

KEYWORDSIschaemic heart disease;

Malonyl CoA;

Malonyl CoA decarboxylase;

Acetyl CoA carboxylase;

AMP-activated protein kinase;

Fatty acid oxidation

1. Introduction

Cardiovascular disease (CVD) is a major health problemworldwide, and it is predicted to be the number one killerby 2010.1 The underlying cause for the majority living withCVD is a diminished oxygen supply to the cardiac muscle,termed ‘ischaemic heart disease’.

Fortunately, epidemiological studies and randomizedclinical trials have provided compelling evidence thatischaemic heart disease is largely manageable.2 Currenttreatment regimens, which consist of either percutaneousor surgical techniques to improve myocardial blood supply,or pharmacotherapy to limit myocardial oxygen demand,have greatly aided in the overall prognosis of ischaemicheart disease patients. Yet, there are still patients whoprove to be ineligible or refractory to conventional treat-ment, and percutaneous or surgical revascularization isassociated with a distinct set of risks. Therefore, newapproaches to treat such patients are necessary. One such

exciting new therapy is the optimization of cardiac energymetabolism.

In the setting of ischaemic heart disease, the generalpremise for the optimization of cardiac energy metabolismis to either stimulate the oxidation of glucose or inhibitthe oxidation of fatty acids for energy production.3 As theoxidation of one molecule of glucose consumes less oxygenthan that of a fatty acid, this allows the heart to produceenergy more efficiently. Furthermore, stimulating glucoseoxidation either directly, or secondarily due to an inhibitionof fatty acid oxidation, results in improved couplingbetween glycolysis and glucose oxidation, which decreasesproton production and alleviates myocardial acidosis,improving cardiac efficiency.4,5

There are numerous ways to inhibit cardiac fatty acid oxi-dation, some of which include2 the inhibition of fatty acidtransport into the cardiac myocyte,3 the inhibition of fattyacid uptake into the mitochondria,4 and the inhibition ofthe enzymatic machinery of the b-oxidative pathwayitself. Although there are existing agents that target allthree of these approaches, this review will focus on theinhibition of mitochondrial fatty acid uptake approach,3

and in particular, the use of agents that increase levels of

* Corresponding author: 423 Heritage Medical Research Center, Universityof Alberta, Edmonton, Canada T6G 2S2. Tel: þ1 780 492 2170; fax: þ1 780492 9753.

E-mail address: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008.For permissions please email: [email protected].

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malonyl CoA, a potent endogenous inhibitor of carnitinepalmitoyltransferase I (CPT-I), the rate-limiting enzyme inthe mitochondrial uptake of fatty acids.6 We will reviewthe literature on the regulation of malonyl CoA via bothits synthesis and degradation, how the malonyl CoA axishas been manipulated in animal models of ischaemia/reperfusion (focusing on the most recent studies involvingtransgenic mice to manipulate malonyl CoA), and thepotential for this axis to be manipulated in humans.

2. Cardiac energy metabolism

In the normal healthy heart, almost all (.95%) ATP gener-ated in the heart comes from mitochondrial oxidative phos-phorylation, with the remainder derived from glycolysis.7

Despite producing more ATP than carbohydrates, fattyacids are not as oxygen-efficient, requiring �10% moreoxygen to produce an equivalent amount of ATP.8 This is ofparticular importance when oxygen becomes a limitingfactor for oxidative metabolism, as seen with ischaemicheart disease. In addition, fatty acids directly inhibit theoxidation of carbohydrates through a phenomenon termedthe ‘Randle cycle’.9 This uncouples glycolysis from glucoseoxidation, which results in an increased proton productionthat reduces cardiac efficiency during reperfusion followingischaemia10 (see 11,12 for review).

As will be discussed, an emerging approach to optimizingcardiac energy metabolism is to keep levels of malonyl CoAhigh in the heart. This inhibits the mitochondrial uptake offatty acids, leading to a subsequent inhibition of fatty acidb-oxidation and secondary increase in glucose oxidation,thereby making oxygen utilization and cardiac energy pro-duction more efficient, while preventing the production ofprotons and development of acidosis.10,11

3. Cardiac carbohydrate metabolism

The metabolism of glucose can be separated into two majorcomponents, glycolysis and glucose oxidation (see 3,8 forreview). Glycolysis results in the production of pyruvateand accounts for ,10% of the total ATP produced by theaerobic heart.13 If glycolysis is coupled to glucose oxidation,the pyruvate generated from glycolysis is converted toacetyl-CoA (which is subsequently oxidized in the TCAcycle) by the enzymatic action of the multi-enzymecomplex, pyruvate dehydrogenase (PDH).

The PDH complex is under tight regulation by an upstreamkinase, PDH kinase, which phosphorylates and inhibits itsactivity.9 This PDH kinase is positively regulated by acetylCoA and NADH. As mitochondrial acetyl CoA/CoA andNADH/NAD ratios are increased by elevated rates of fattyacid oxidation, it leads to a potent inhibition of PDH andglucose oxidation. This phenomenon was first describedby Randle et al.9 in the 1960s and has been termed the‘Randle cycle’.

4. Cardiac fatty acid metabolism

Fatty acids enter the cardiac myocyte by either passive dif-fusion or protein-mediated transport across the sarco-lemma14 (see 3,8 for review). Once transported across thesarcolemma, fatty acids are subsequently activated byesterification to fatty acyl CoA by fatty acyl CoA synthetase.

This acyl CoA can either be esterified to intracellular lipidsor converted to long-chain fatty acyl carnitine by CPT-I.7

Fatty acid b-oxidation occurs predominantly in the mito-chondria and to a smaller extent in the peroxisomes.15 Formitochondrial fatty acid b-oxidation to begin, the cyto-plasmic long-chain fatty acyl CoA must first be transportedinto the mitochondrial matrix through a carnitine-dependent transport system.8,16 This carnitine transportsystem involves three enzymes: CPT-I, carnitine acyltranslo-case, and CPT-II. Of these three enzymes, CPT-I is rate limit-ing in regard to mitochondrial fatty acid uptake and issubject to potent inhibition via malonyl CoA, the compoundwhose regulation will be the major focus of this review.6

Once in the mitochondria, b-oxidation repeatedly cleavesoff two carbon acetyl CoA units from fatty acyl CoA, gener-ating NADH and reduced flavine adenine dinucleotide in theprocess. The b-oxidation process involves four enzymaticallycatalysed reactions, with the last step regenerating acyl CoAfor another round of b-oxidation and releasing acetyl CoAfor the citric acid cycle. As mentioned earlier, oxidation offatty acids increases the acetyl CoA/CoA ratio, which inhi-bits PDH and glucose oxidation.

5. Regulation of malonyl CoA

As mentioned previously, malonyl CoA is a potent endogen-ous inhibitor of CPT-I, the rate-limiting enzyme in the mito-chondrial uptake of fatty acids. Thus, malonyl CoAdecreases the uptake of fatty acids into the mitochondria,thereby reducing mitochondrial fatty acid b-oxidation.Because the turnover of malonyl CoA is quite rapid, witha half life of �1.25 min,17 both the production and thedegradation of malonyl CoA control its levels, and thereforeof fatty acid oxidation rates.

The production of malonyl CoA is primarily attributed tothe enzymatic activity of acetyl CoA carboxylase (ACC),which catalyses the carboxylation of acetyl CoA to malonylCoA (Figure 1).18,19 There are two isoforms of ACC in theheart, a and b, with a predominance of ACCb.19 This leadsto the suggestion that the malonyl CoA produced by thisisoform is more involved in the regulation of fatty acid oxi-dation, as opposed to the high abundance of ACCa in theliver, where the malonyl CoA produced by this isoform ismore involved in the regulation of fatty acid synthesis.Studies from our laboratory have confirmed the key role ofACCb in regulating cardiac fatty acid oxidation.20 The regu-lation of ACC is under phosphorylation/dephosphorylationcontrol, with 50AMP-activated protein kinase (AMPK) havinga major role in its regulation in the heart (Figure 1).21,22

As will be discussed in the following section, this AMPK regu-lation of ACC becomes very important during times of energystarvation in the heart, as seen in ischaemia/reperfusion.

Until recently, it was much less clear as to what enzymesmight be responsible for the degradation of malonyl CoA.One enzyme that has emerged as being important in control-ling cardiac malonyl CoA degradation is malonyl CoA decar-boxylase (MCD), whose catalytic activity is responsible forthe decarboxylation of malonyl CoA back into acetyl CoA(Figure 1).23 Studies in both rat and mouse have demon-strated that MCD is indeed involved in regulating cardiacmalonyl CoA levels, and that inhibition of MCD can limitrates of fatty acid oxidation, leading to a secondary increasein glucose oxidation (Figure 2). This decrease in fatty acid

J.R. Ussher and G.D. Lopaschuk260

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oxidation and increase in glucose oxidation are also associ-ated with an improvement in the functional recovery ofthe heart during ischaemia/reperfusion injury.12,24–26 Inaddition, peroxisome proliferators-activated receptoralpha (PPARa), which is a major transcription factor involved

in the regulation of fatty acid oxidation, has been shown toregulate the expression of MCD.27,28

Previous work in our laboratory has demonstrated that thehigh rates of fatty acid oxidation observed during reperfu-sion are attributed to a dramatic reduction in the levels of

Figure 1 The regulation of malonyl CoA in the heart and its alterations during ischaemia/reperfusion. Malonyl CoA is synthesized via acetyl CoA carboxylase,which carboxylates acetyl CoA into malonyl CoA. Malonyl CoA is degraded via malonyl CoA decarboxylase, which decarboxylates malonyl CoA back into acetylCoA. In addition, acetyl CoA carboxylase is negatively regulated by phosphorylation via 50AMP-activated protein kinase. Increased production of malonyl CoAinhibits mitochondrial uptake of fatty acids through carnitine palmitoyltransferase I, thereby reducing rates of fatty acid b-oxidation. During ischaemia,decreased ATP production and a subsequent increase in AMP lead to a rapid activation of 50AMP-activated protein kinase, which phosphorylates and inhibitsacetyl CoA carboxylase, resulting in a dramatic drop in malonyl CoA levels. Following aerobic reperfusion of the ischaemic heart, 50AMP-activated proteinkinase activity is sustained, while malonyl CoA decarboxylase activity is maintained. This keeps malonyl CoA levels low, allowing fatty acids to dominate asthe main source of oxidative ATP production, at the expense of glucose oxidation, which increases the production of lactate and protons observed duringreperfusion.

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malonyl CoA, as opposed to direct alterations in the charac-teristics of CPT-I.21 In addition, we have shown that thisreduction in malonyl CoA levels is associated with a rapidactivation of AMPK during ischaemia, which persists intoreperfusion, causing the phosphorylation-induced inacti-vation of ACC (Figure 1).21 It has also been suggested that

MCD is a direct target of AMPK, but our laboratory hasbeen unable to reproduce that data.29 In summary,decreased ACC activity via AMPK phosphorylation, coupledwith a maintained MCD activity, is a key factor responsiblefor the rapid decrease in cardiac malonyl CoA levelsobserved during ischaemia/reperfusion.

Figure 2 Targeting of the malonyl CoA axis to improve ischaemia/reperfusion injury. Novel malonyl CoA decarboxylase inhibitors prevent the degradation ofmalonyl CoA, keeping malonyl CoA levels high during reperfusion, thereby preventing the uptake and subsequent oxidation of fatty acids in the mitochondria.This reduces mitochondrial acetyl CoA/CoA and NADH/NAD ratios, thus alleviating the fatty acid-induced inhibition of pyruvate dehydrogenase via the ‘Randlecycle’. Increased pyruvate dehydrogenase activity increases the oxidation of pyruvate, improving the coupling between glycolysis and glucose oxidation, redu-cing lactate and proton production. This decrease in proton production alleviates the acidosis seen during reperfusion, allowing ATP in the heart to be used forcontractile purposes as opposed to restoring ionic homeostasis, which improves cardiac functional recovery and overall efficiency.


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Cardiac malonyl CoA levels can also increase secondary toan increase in glucose oxidation. Previous work demon-strated that the acetyl CoA produced by PDH was moreaccessible to carnitine acetyltransferase than that producedfrom fatty acid b-oxidation.30 Thus, we hypothesized andshowed that increased glucose oxidation could increasecytosolic acetyl CoA supply for ACCb, increasing malonylCoA levels that then inhibit fatty acid b-oxidation.20

It is of interest to note that although malonyl CoA is apotent inhibitor of CPT-I, the majority of malonyl CoA inthe heart is inaccessible to CPT-I. The cytosolic concen-tration of malonyl CoA in the heart is �5 mM, whereas theIC50 of CPT-I inhibition via malonyl CoA is between 50 and100 nM.20,31 Therefore, if all the malonyl CoA in the heartwere accessible to CPT-I, fatty acid oxidation would alwaysbe completely inhibited, which of course is not the case.The reason why the majority of malonyl CoA is not accessi-ble to CPT-I is not known, but may have to do with compart-mentation of malonyl CoA. Recent evidence supporting thismay come from the observation that a large proportion ofMCD exists in the peroxisomes.32 In addition, it has beensuggested that the majority of malonyl CoA produced inthe heart originates from the peroxisomes.33

6. Cardiac energy metabolism duringischaemia/reperfusion

Cardiac energy metabolism is drastically altered duringischaemia, starting with an acceleration of glycolysis, inan attempt to provide an anaerobic source of ATP to makeup for the reduction in oxidative ATP production. Also ofimportance is that fatty acids dominate as the substratefor what residual oxidative metabolism remains in theoxygen-deprived ischaemic heart,34 at the expense ofglucose oxidation. This results in an uncoupling between gly-colysis and glucose oxidation, contributing to the acidosisobserved in the ischaemic heart, which reduces cardiacefficiency.4,10

During reperfusion of the ischaemic heart, glycolytic ratesremain elevated, while fatty acids dominate as a source foroxidative energy production.10 These high rates of fatty acidmetabolism can account for .90% of energy production inthe reperfused heart, and this results in a drastic inhibitionof glucose oxidation. Thus, similar to ischaemia, reperfusionof the ischaemic heart is accompanied by an increased pro-duction of protons that lowers cardiac efficiency. A majorfocus of this review has been the emphasis that high ratesof fatty acid oxidation can cause myocardial acidosis byuncoupling glucose oxidation from glycolysis. Althoughother studies have suggested that acidosis may protect theheart during reperfusion by reducing contractile force35–38

to preserve the viability of hibernating myocardium, orkeeping the mitochondrial permeability transition pore ina closed state,39,40 such matters are beyond the scope ofthis review.

The reason for the excessive use of fatty acids as a sourceof fuel during and following ischaemia is primarily the resultof two factors: (1) plasma levels of fatty acids increase dra-matically during and following ischaemia,41–44 and (2) sub-cellular changes occur in the heart itself, resulting in adecreased control over fatty acid oxidation.21,45 In particu-lar, the levels of malonyl CoA decrease in the heart due to

the rapid activation of AMPK during ischaemia, which per-sists into reperfusion, resulting in the phosphorylationinduced inhibition of ACC.11,21,23,45 This leads to the accel-erated mitochondrial uptake of fatty acids and subsequentoxidation.

7. Targeting the malonyl CoA axis to treatcardiac ischaemia

There are a number of ways to manipulate malonyl CoA inthe heart, which include manipulation of the enzymesinvolved in regulating its production, i.e. AMPK, ACC, andMCD. The following sections will examine each of thelatter three enzymes individually as potential treatmentsfor ischaemia/reperfusion in more detail.

7.1 Targeting 50AMP-activated protein kinaseto treat ischaemia/reperfusion

Since its initial identification in 1988 by Sim and Hardie,46

AMPK has become a protein, with wide interest amongmany investigators, due to its ability to increase energymetabolism in times of stress. In regard to the stress ofischaemia/reperfusion injury, many groups have postulatedthat AMPK activation would be beneficial in this scenariovia increasing glucose uptake to provide an anaerobicsource of ATP for the energy-starved heart.47–49 However,our group previously showed that AMPK activity candecrease cardiac malonyl CoA and increase fatty acid oxi-dation in the ischaemic heart.21 We therefore hypothesizedthat inhibition of AMPK would be beneficial for ischaemia/reperfusion injury by increasing malonyl CoA levels andreducing fatty acid oxidation rates, thereby alleviatingmyocardial acidosis. Supporting the former proposal,isolated working heart studies in a transgenic mouse modelof a dominant negative (DN) AMPKa2 with nearly a completeloss of myocardial AMPK activity have been shown to recoverworse during reperfusion following a low-flow ischaemia.50

Hearts from the transgenic DN-AMPKa2 mice were unableto increase GLUT4 translocation and glucose uptakeduring the low-flow ischaemia or reperfusion periods, andthey had accelerated rates of apoptosis as indicated byincreased caspase 3 cleavage and TUNEL staining.However, DN-AMPKa2 transgenic mice had significantcontractile dysfunction compared with wild-type mice inthe normal setting, which may explain why they did notrecover as well during ischaemia/reperfusion. Furthermore,there were no differences in myocardial metabolismbetween the control and DN-AMPKa2 transgenic mice,which suggests that there may have been no differences inmalonyl CoA levels from the hearts of these animals.

Another study investigating the beneficial effects ofadiponectin during ischaemia/reperfusion injury noted areduced phosphorylation of AMPK at its threonine 172residue (which is necessary for AMPK activation) in anadiponectin-deficient mouse model 48 h after a 30 minocclusion of the left anterior descending (LAD) coronaryartery.51 The authors demonstrated that inhibition of AMPKprevented the anti-apoptotic effects of adiponectin oncardiac myocytes and fibroblasts subjected to hypoxia/reox-ygenation. Nonetheless, the anti-apoptotic effects of AMPKwere performed only in culture, and the beneficial effectsof adiponectin during reperfusion following LAD occlusion


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could also be explained via cyclooxygenase II-dependenteffects.

More recently, a study in an AMPKa2 subunit-deficientmouse model reported that although AMPKa2 deficiencyaccelerated the appearance of contracture during ischae-mia, there was no effect on reperfusion recovery of thesehearts, suggesting that inhibition of AMPK is not detrimentalin the heart as an earlier study had reported.52 Moreover,the perfusions in this study were glucose-only perfusions,and thus high rates of fatty acid oxidation would not be aproblem in ischaemia/reperfusion. It is possible that thebeneficial effect of reducing the extremely high rates offatty acid oxidation during reperfusion may have beenmasked because of this.

The regulation of AMPK by its upstream kinases, the AMPKkinases (AMPKKs), likely plays an important role in activatingAMPK during ischaemia/reperfusion. Previous work in ourlaboratory has shown that although AMPK is activated inthe rat heart during reperfusion following ischaemia, myo-cardial levels of AMP quickly return to normal. Thus,alternative mechanisms of AMPK activation likely existoutside of changes in AMP levels. One possibility is AMPKK,which phosphorylates and activates AMPK. IdentifiedAMPKKs include the tumour-suppressor LKB1, calmodulin-dependent protein kinase kinase b (CamKKb), and morerecently, transforming growth factor-activatedkinase-1.22,53,54 Our group55 and others47 have shown thatAMPKK is rapidly activated in the ischaemic heart. To date,the only AMPKK that has been extensively studied in theheart is LKB1. We have shown that AMPKK activationduring ischemia is not due to LKB1 activation.55 In contrast,a previous study investigating the role of LKB1 on AMPK acti-vation in the heart during ischaemia and anoxia reportedthat LKB1 was responsible for phosphorylating and activatingthe AMPKa2 subunit at its threonine 172 residue, but not theAMPKa1 subunit.56 Although hearts from these mice hadenlarged atria and reduced weights, echocardiographicassessment revealed no cardiac dysfunction. However,these studies did not examine functional differencesduring reperfusion, and perfusions were again performedwith glucose as the sole substrate. Further studies are there-fore required to determine what role LKB1 and the otherAMPKKs have on AMPK during ischaemia/reperfusion,malonyl CoA levels, and functional recovery.

Another way to inhibit AMPK is via insulin administration.A number of studies have examined the role of glucose–insulin–potassium (GIK) for the treatment of acute myocar-dial infarction.57–59 We initially hypothesized that insulinwould benefit the aerobically reperfused ischaemic heart.This would arise from the inhibition of myocardial AMPKduring ischaemia and subsequent reperfusion, thereby redu-cing rates of fatty acid oxidation and increasing glucose oxi-dation rates, alleviating myocardial acidosis and improvingfunctional recovery. Unfortunately, the majority of studiesexamining the beneficial effects of insulin on functionalrecovery of the heart during reperfusion have performedtheir perfusions with glucose as the sole substrate. Arecent study in our laboratory has demonstrated that fattyacids in the perfusate interfere with insulin’s ability toinhibit AMPK, and although insulin is still able to reducefatty acid oxidation, a greater stimulation of glycolysisthan glucose oxidation actually increases proton productionand worsens functional recovery during reperfusion.60

Therefore, it is unlikely that any beneficial effects ofinsulin during reperfusion involve an inhibition of AMPK,and it is possible that our previous results can explain thelack of mortality benefit with GIK for patients undergoingan acute myocardial infarction during the recent CREATE-ECLA trial.61 In fact, a recent study suggests that GIK mayactually increase mortality in the early post-AMI period.62

Owing to the limitations of the first two studies, and theresults of the aforementioned third study, we believe thatthere is insufficient evidence to state that AMPK activationis beneficial during ischaemia/reperfusion injury. What isneeded to reconcile these discrepancies is more studiesdone using in vivo ischaemia/reperfusion models investi-gating the effect of AMPK on myocardial function, as wellas actual measurements of myocardial malonyl CoA inthese systems.

7.2 Targeting acetyl CoA carboxylase to treatischaemia/reperfusion

In regard to ACC, there is very little literature investigatingits effects on ischaemia/reperfusion, as the majority of lit-erature on ACC modulation has focused on inhibiting ACCin the liver and adipose tissue. It has been postulated thatinhibiting ACC in these tissues to decrease malonyl CoAwould decrease fatty acid biosynthesis.63–65 Unfortunately,no studies have investigated the effects of ACC inhibitionon cardiac function. There are no selective pharmacologicalinhibitors of ACC available, and they would have to bespecific to the b-isoform, which predominates in the heartand is more tightly linked to the regulation of fatty acid oxi-dation.20 Nonetheless, mice deficient for ACCb are availableand have been characterized and show significant increasesin fatty acid oxidation.66 It would be of interest to conductischaemia/reperfusion studies in these mice, as it is possiblethat hearts from these mice would have a depressed recov-ery of cardiac function during ischaemia/reperfusion due tohigh rates of fatty acid oxidation and subsequent acidosis.

7.3 Targeting malonyl CoA decarboxylaseto treat ischaemia/reperfusion

Recent studies in our laboratory have shown that MCD is amajor regulator of fatty acid oxidation rates in the heart,and that inhibition of this enzyme is a viable target for thetreatment of ischaemia/reperfusion injury.25,26 First, usingnovel inhibitors of MCD, we have shown that inhibition ofMCD in an isolated working rat heart perfusion system signifi-cantly increases malonyl CoA levels.26 This was associatedwith a significant decrease in fatty acid oxidation ratesand a subsequent increase in glucose oxidation rates.These metabolic effects induced via inhibition of MCDcaused a significant reduction in proton production duringboth the aerobic setting and during low-flow ischaemia.Furthermore, inhibition of MCD resulted in a significantimprovement in cardiac functional recovery of aerobicallyreperfused ischaemic rat hearts. Another study from ourlaboratory and Stanley’s demonstrated in an in vivo pigmodel of demand-induced ischaemia that MCD inhibitiononce again significantly increased malonyl CoA levelsand glucose oxidation rates.24,26 Moreover, this wasaccompanied by a significant reduction in myocardiallactate production and a complete restoration of leftventricular work. Last, a third study from our laboratory


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investigated the effects of chronic MCD inhibition in awhole-body MCD-deficient mouse model.25 Although heartsfrom these animals had a significant increase in malonylCoA levels, isolated aerobic working heart perfusionsdemonstrated no differences in glucose and fatty acidmetabolism compared with control hearts. This may havebeen attributed to the significant upregulation in themRNA of a number of different PPARa target transcriptssuch as CD36 and CPT-I. Nonetheless, when hearts fromthe MCD-deficient mice were subjected to the stress ofischaemia/reperfusion injury, a significant improvement inthe recovery of cardiac power and function was observed.This enhanced recovery was associated with a significantincrease in glucose oxidation rates, whereby glucoseoxidation became the major source of ATP production inthe heart. Thus, hearts from the MCD-deficient micehad improved coupling between glycolysis and glucoseoxidation, reduced proton production, and less myocardialacidosis.

As mentioned earlier, although the inhibition of fatty acidoxidation in the heart improves function in the setting ofischaemic heart disease, others have postulated that theinhibition of fatty acid oxidation in peripheral tissues, suchas the muscle and liver, will exacerbate insulin resistanceand type 2 diabetes.67 This is an important point to consider,a significant number of patients with ischaemic heartdisease are also obese/type 2 diabetic. From a clinicalstandpoint, oral delivery of MCD inhibitors for the prophy-lactic treatment of ischaemic heart disease would be practi-cal. However, this would affect the peripheral tissues suchas the muscle, and could cause insulin resistance orworsen the diabetic state. A recent collaboration by our lab-oratory and that of Muoio and colleagues68 has shown thatthis is not the case. Obesity and insulin resistance inducedby high-fat diet are actually accompanied by increasedrates of incomplete fatty acid oxidation as opposed toimpaired fatty acid oxidation.68 In fact, we demonstratedthat the MCD-deficient mouse was protected fromobesity-induced insulin resistance, which was associatedwith decreased rates of incomplete fatty acid oxidation.Furthermore, potential toxic intramuscular fatty acidmetabolites that have been postulated to cause insulinresistance due to impaired fatty acid oxidation, such aslong-chain acyl CoAs, actually trended to increase in theMCD KO mice, suggesting that they are not direct mediatorsof insulin resistance.

As mentioned earlier, MCD expression is transcriptionallyregulated by PPARa.27,28 Thus, manipulating PPARa offersanother approach to regulating malonyl CoA levels andrates of fatty acid oxidation. Indeed, previous work in ourlaboratory has shown that hearts from mice deficient forPPARa have reduced expression of MCD and increasedlevels of malonyl CoA.69 These animals subsequently havelower rates of fatty acid oxidation and increased rates ofglucose oxidation. Moreover, PPARa-deficient mice have animproved recovery of cardiac power during reperfusion fol-lowing a global no-flow ischaemia, whereas mice overex-pressing PPARa have a worse recovery of cardiac powerunder identical conditions.70 These results are contrary toreports utilizing acute systemic activation of PPARa withligands that caused beneficial effects against ischaemia/reperfusion injury.71,72 The benefit seen with PPARa inhi-bition could be due to the optimization of cardiac energy

metabolism during reperfusion, whereas the benefit seenwith PPARa activation could be the result of its anti-inflammatory properties.73–75 Because PPARa has anti-inflammatory properties and regulates the expression ofmany genes involved in fatty acid uptake and oxidationbesides MCD,73,76,77 inhibiting MCD to decrease fatty acidoxidation in the heart may be a more plausible approachthan inhibiting PPARa.

8. The potential for malonyl CoA axismanipulation in humans

Currently, there are a number of agents used clinically thatoptimize cardiac energy metabolism. This includes, trimeta-zidine, a 3-ketoacyl CoA thiolase inhibitor. The Cochranecollaboration meta-analysis recently showed trimetazidineto be an effective therapy for stable angina compared withplacebo (�40% reduction in the mean number of anginaattacks per week), alone or combined with conventional anti-anginal agents.78 In addition, perhexiline, a CPT-1 inhibitor,has been shown to have clinical utility in refractory anginapectoris,79 aortic stenosis,80 and chronic heart failure,81

where it improves symptomatic status, left ventricular ejec-tion fraction, and quality of life. Direct stimulation of glucoseoxidation with dichloroacetate, a PDH kinase inhibitor,improves left ventricular stroke volume and cardiac efficiencyin the setting of heart failure.82

To date, there are no agents clinically available for thetreatment of ischaemia/reperfusion injury that target themalonyl CoA axis to optimize cardiac energy metabolism.On the basis of the positive human trials with trimetazidine,a direct fatty acid b-oxidation inhibitor, and the positiveresults seen with both acute and chronic MCD inhibition inanimals, manipulating the malonyl CoA axis in humansappears plausible and could yield positive effects for thetreatment of ischaemia/reperfusion injury. In regard toMCD inhibition, two potential setbacks are that CPT-1 inhi-bition has been shown in past studies to cause hypertrophy,and that MCD deficiency in humans is associated with cardi-omyopathy.83 A number of studies in the early 1980sreported that chronic treatment in dogs and rats with theCPT-1 inhibitor, oxfenicine, results in the development ofcardiac hypertrophy.84,85 However, more recent studieshave actually shown that the CPT-1 inhibitors, oxfenicineand etomoxir, can actually delay adverse left ventricularmodelling in a dog model of pacing-induced heart failure86

and rat model of aortic constriction.87 Some of the reporteddiscrepancy may lie in the fact that the earlier studies didnot address whether physiological or pathological hypertro-phy was occurring. Furthermore, these inhibitors of CPT-1were irreversible, whereas manipulating malonyl CoA viaMCD would be an indirect inhibition of CPT-1. In addition,MCD-deficient mice have normal cardiac function and showno signs of cardiac hypertrophy.26 To address the cardiomyo-pathy issue, only 18 patients with MCD deficiency have beenreported in the literature,88 and of these 18, only five devel-oped a cardiomyopathy.83,88–92 Of further interest, in thosepatients who completely lack MCD, no cardiomyopathieswere observed, and those patients deficient in MCD thatdeveloped cardiomyopathies often possessed mutations inthe gene that result in subcellular mistargeting and notthe complete absence of MCD protein.92 Therefore,


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inhibition of MCD in the heart appears to be safe, and futurestudies are warranted to explore the role of MCD inhibitionas a therapy for ischaemic heart disease. As of yet, thereare no studies looking at regulating the malonyl CoA axisvia ACC in the heart to warrant manipulation of thisenzyme in human studies of ischaemia/reperfusion. More-over, animal studies of AMPK manipulation have yet to inves-tigate the effects of AMPK on malonyl CoA levels in theheart, and results of AMPK’s effects on cardiac functionare mixed. Thus, further work in animal models is necessarybefore AMPK manipulation is used as a therapeutic target inhumans for ischaemia/reperfusion injury.

9. Summary

The optimization of cardiac energy metabolism representsan exciting new therapeutic approach for the treatment ofischaemia/reperfusion injury. One approach to optimizecardiac energy metabolism is to regulate the levels ofmalonyl CoA, a potent endogenous inhibitor of cardiacfatty acid oxidation, secondary to its inhibition of CPT-1,the rate-limiting enzyme in the mitochondrial uptake offatty acids. A number of studies have recently been pub-lished showing that the inhibition of MCD increases cardiacmalonyl CoA levels. These studies reported improved func-tional recovery of the heart during ischaemia/reperfusioninjury, which was attributed to increased glucose oxidationand decreased proton production. Thus, targeting themalonyl CoA axis in the heart represents a potential excitingnew therapy for the treatment of ischaemic heart disease.

Conflict of interest: J.R.U. is a trainee of the Alberta HeritageFoundation for Medical Research and Tomorrow’s Research Cardio-vascular Health Professionals (TORCH). G.D.L. is a medical scientistof the Alberta Heritage Foundation for Medical Research. J.R.U. hasno conflicts to declare. G.D.L. is the President and CEO of MetabolicModulators Research Ltd, a company which has interests in develop-ing metabolic drugs to treat heart disease. This includes agents thatmodify the malonyl CoA axis.

Funding

Supported by a grant from the Canadian Institutes for HealthResearch Grant to G.D.L.

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