Heart failure is one of the leading causes of death worldwide and has been singled
out as an emerging epidemic.1, 2 With a 5‐year survival rate of 50%, heart failure
poses a tremendous burden on our economic and healthcare system. Despite extensive
interests and paramount clinical needs, our understanding of heart failure remains
incomplete. As a consequence, there is currently no cure.
Hypertension is one of the most important risk factors of heart failure. Under high
blood pressure, cardiac ventricular wall stress is mounted. According to Laplace's
law, an increase in cardiac wall thickness can effectively ameliorate wall stress.3
This so‐called concentric cardiac growth is achieved by upregulation of sarcomere
biosynthesis and enlargement of individual cardiac myocytes attributed to limited
replicative capacity in the adult heart. In response to persistent stress, however,
this once adaptive hypertrophic growth may progress into decompensation and heart
failure. Over the past few decades, numerous signaling molecules and pathways have
been identified in cardiac hypertrophic growth and heart failure.4 These processes
involve extensive cardiac remodeling in metabolism, structure, and electrophysiology.
Growing evidence indicates that metabolic remodeling precedes most, if not all, other
pathological alterations and likely plays an essential role in cardiac hypertrophy
and heart failure.5, 6, 7, 8, 9, 10 Ischemic heart disease is another critical contributing
factor to heart failure. Patients surviving myocardial infarction (MI) may undergo
extensive pathological remodeling in the heart with major metabolic derangements.
Here, we review recent findings of cardiac metabolic changes in response to hemodynamic
stress and cardiac ischemia with a focus on glucose utilization. We also discuss potential
therapeutic targets from carbohydrate metabolic pathways to tackle this devastating
heart disease.
Glucose Metabolism in the Heart
The heart is an omnivore, consuming fuel constantly and using any substrate available.8
The high rates of ATP production and turnover are critical in maintaining cardiac
contractility to deliver blood and oxygen to the other organs. Under normal conditions,
cardiac ATP is mainly derived from fatty acid (FA) oxidation (FAO), with glucose metabolism
contributing less. However, under stress conditions, FAO may be reduced, which is
concomitant with increased glucose utilization.9 Glucose uptake in cardiomyocytes
is mediated by glucose transporters (GLUTs), with GLUT1 and GLUT4 as the most abundant
isoforms.11, 12, 13, 14, 15, 16 Whereas GLUT1 is highly expressed in the fetal heart,
GLUT4 is predominant in the adult heart. Inside cardiac myocytes, glucose may be first
phosphorylated to glucose 6‐phosphate by hexokinase or converted to sorbitol by the
polyol pathway. Glucose 6‐phosphate subsequently goes through multiple metabolic pathways,
including glycolysis, pentose phosphate pathway (PPP), and the hexosamine biosynthetic
pathway (HBP; Figure 1).6 Pathological alterations of these pathways in cardiac hypertrophy
and ischemic heart disease are associated with impaired signaling transduction, perturbed
ion and redox homeostasis, and contractile dysfunction.
Figure 1
Glucose metabolic pathways in the heart. In cardiomyocytes, glucose is transported
through glucose transporters GLUT1 or GLUT4. Polyol pathway‐derived sorbitol and fructose
may be converted to AGEs or fructose 6‐P for glycolytic use. Intracellular glucose
can be phosphorylated to glucose 6‐phosphate by hexokinase (HK). Glucose 6‐phosphate
is then metabolized bv multiple pathways, including glycolysis, pentose phosphate
pathway (PPP), and hexosamine biosynthetic pathway (HBP). In the cytosol, pyruvate
can be utilized to form alanine or lactate. In mitochondria, pyruvate is converted
to acetyl‐CoA for the tricarboxylic acid cycle. Ribulose 5‐P derived from PPP can
be used for pyrimidine/purine synthesis or converted into intermediates of glycolysis.
UDP‐GlcNAc, the final product of HBP, serves as a substrate for the synthesis of proteoglycans,
hyaluronan, glycolipid, GPI anchor, O‐GlcNAc modification, and N‐glycan. AGEs indicates
advanced glycation end products; fructose 6‐P, fructose 6‐phosphate; GLUT, glucose
transporter; glyceraldehyde 3‐P, glyceraldehyde 3‐phosphate; GPI, glycosylphosphatidylinositol;
O‐GlcNAc, O‐linked β‐N‐acetylglucosamine; ribulose 5‐P, ribulose 5‐phosphate; UDP‐GlcNAc,
uridine diphosphate N‐acetylglucosamine.
Glycolysis
Glycolysis is arguably the most important route for glucose metabolism in a cell,
which produces pyruvate, NADH, and ATP. ATP yield from glycolysis, however, contributes
only a small portion of the overall ATP pool in the normal heart.17 In cytosol, pyruvate
can be further utilized to form alanine by alanine transaminase or reduced to lactate
by lactate dehydrogenase. On the other hand, pyruvate is oxidized (known as pyruvate
oxidation or glucose oxidation) to generate acetyl‐CoA by pyruvate dehydrogenase that
fuels the tricarboxylic acid cycle in mitochondria. Three enzymes, including hexokinase,
phosphofructokinase (PFK), and pyruvate kinase, catalyze irreversible reactions of
glycolysis; thus, they are proposed as critical enzymes in governing glycolysis.18
The control of glycolysis is variably distributed between enzymes and counts on the
substrate, hormone, oxygen deficiency, or other different conditions.19 Hexokinase
is the first enzyme of glycolysis. Its control of glucose transport is abrogated in
the presence of insulin whereas its usage of glucose is favored in the presence of
ketones. The second regulatory enzyme of glycolysis is PFK that has 2 isoforms: PFK1
and PFK2. Fructose 6‐phosphate is converted to fructose 1,6‐bisphosphate and fructose
2,6‐bisphosphate (fructose 2,6‐BP) by PFK1 and PFK2, respectively (Figure 2). Fructose
2,6‐BP is a potent activator of PFK1 for production of fructose 1,6‐bisphosphate and
following glycolytic flux.20 Pyruvate kinase, the final enzyme of glycolysis, regulates
the flux from this pathway. Its control of glycolysis is increased during cardiac
perfusion with glucose in the presence of ketones or insulin or both.19 Studies have
shown that glycolysis plays a crucial role in maintaining contractile function attributed
to the tight coupling of glycolysis‐derived ATP with ion pump ATPase.21
Figure 2
The glycolysis pathway in the heart. A series of enzymatic reactions of glycolysis
convert glucose to pyruvate, which may be reduced to lactate or further catabolized
by the TCA cycle. Glycolysis‐derived ATP plays a crucial role in maintaining the contractile
function of the heart. The green arrow indicates activation of PFK1 by fructose 2,6‐biphosphate.
ALT indicates alanine transaminase; fructose 1,6‐BP, fructose 1,6‐bisphosphate; fructose
2,6‐BP, fructose 2,6‐bisphosphate; fructose 6‐P, fructose 6‐phosphate; GAPDH, glyceraldehyde
3‐phosphate dehydrogenase; GLUT, glucose transporter; glyceraldehyde 3‐P, glyceraldehyde
3‐phosphate; HK, hexokinase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase;
PFK, phosphofructokinase; PK, pyruvate kinase; TCA, tricarboxylic acid.
Glycolysis in the Hypertrophic Heart
During cardiac hypertrophic growth and pathological remodeling, there is a prominent
metabolic shift from FAO to glucose utilization. This alteration is associated with
an increase in glycolysis in hypertrophied hearts (Table).22, 23, 24, 25 At the mechanistic
level, intracellular free AMP in the cardiomyocyte is increased when the heart faces
pressure overload, which consequently transduces signaling through AMP‐activated protein
kinase. As a result, synthesis of fructose 2,6‐BP, an activator of PFK1, is upregulated
and glucose transporter migration to sarcolemmal membrane is enhanced.23 Consistently,
a transgenic mouse model overexpressing kinase‐deficient PFK2 in cardiomyocytes has
reduced glycolysis attributed to the low level of fructose 2,6‐BP.24 These mice exhibit
more‐profound hypertrophy, elevated fibrosis, and cardiac dysfunction than control
animals in response to pressure overload.25 Failure to increase fructose 2,6‐BP and
glycolysis may therefore contribute to the deleterious structural and functional changes
in the heart. Taken together, elevation of glycolysis through activation of fructose
2,6‐BP and PFK1 is an adaptive response to cardiac pressure overload. The increase
in glycolysis is, however, accompanied by reduced or normal glucose oxidation, which
may lead to an uncoupling between glucose uptake and oxidation. This imbalance has
been implicated in pathological hypertrophic remodeling in the heart.22
Table 1
Phenotypes of the Animal Models in Which Glucose Metabolism Is Altered
Animal Model
Background
Condition
Events
Cardiac Outcome
References
Cardiac‐specific knockout of GLUT4
C57BL/6, FVB
Baseline
↑Insulin‐independent glucose uptake
↓Insulin‐dependent glucose uptake
Mild hypertrophy
12
I/R
↓Glycolysis
↑I/R injury
13
Cardiac‐specific overexpression of GLUT1
FVB
Baseline
↑Insulin‐independent glucose uptake
↑Glycolysis
Normal
14
8 wks post‐TAC
↔Myocardial energetics
↓Cardiac dysfunction
↑Long‐term survival rate
Inducible cardiac‐specific overexpression of GLUT1
FVB
Baseline (6–10 wks old)
↑Glucose utilization, glycolysis
Normal
15
4 wks post‐TAC
↑Glucose oxidation, [G‐1‐P], [lactic acid], [glycogen], ATP synthesis
↑FA metabolism, OXPHOS genes
↓Fibrosis
↑Cardiac hypertrophy
Cardiac‐specific knockout of GLUT1
C57BL/6
Baseline (6–10 wks)
↓Glycolysis, glucose oxidation
↑FAO
Normal
16
4 wks post‐TAC
↓Glycolysis, glucose oxidation
↑FAO
↔Hypertrophy
↔Mitochondrial function
Cardiac‐specific kinase‐deficient PFK‐2
FVB
Baseline (3–4 m)
↓Glycolysis, [F‐2,6‐P2], [F‐1,6‐P2]
↑[G‐6‐P], [F‐6‐P], [UDP‐GlcNAc], [glycogen]
↓Insulin sensitivity
Mild hypertrophy
↑Fibrosis
↓Cardiac function
24
13 wks post‐TAC
↓[F‐2,6‐P2], glycolysis
↑Cardiac hypertrophy
↑Fibrosis, cardiac dysfunction
25
WT
FVB/NJ
4 wks of treadmill training
↓Glycolysis, PFK activity, acute
↑Glycolysis, PFK activity, recovered
↑Physiological hypertrophy
↑Cardiac function
26
Cardiac‐specific kinase‐deficient PFK‐2
Baseline (15–16 wks old)
↓Glycolysis, PFK activity
↑Physiological hypertrophy
↑Cardiac function
Cardiac‐specific phosphatase‐deficient PFK‐2
Baseline (15–16 wks old)
↑Glycolysis
↑Pathological hypertrophy
Cardiac‐specific phosphatase‐deficient PFK‐2
FVB/NJ
Baseline (3–4 m)
↑Glycolysis, [F‐2,6‐P2]
↓[G‐6‐P], [glycogen], FAO
↑Cardiac hypertrophy, fibrosis
↓Hypoxia‐induced contractile inhibition in cardiomyocytes
31
I/R
↔Insulin sensitivity
↔Myocardial infarct size
AR‐null mice
C57BL/6
Base line (14–16 wks old)
↓Ejection fraction, slightly
63
2 wks post‐TAC (12–16 wks old)
↑Lipid peroxidation‐derived aldehydes
↑Aldehyde‐modified proteins
↑Autophagy
↑Pathological cardiac hypertrophy
↓Cardiac function
Cardiac‐specific overexpression of human AR
C57BL/6
Baseline (3 m)
↔Glucose uptake
↔GLUT1, GLUT4, CPT1, AOX mRNA
↑SDH mRNA level
Normal
79
Baseline (12 m)
↓FA metabolism
↑Cardiac dysfunction
I/R
↓ mRNA levels of FA metabolism related genes
↑ROS
↑Infarct size, apoptosis
↑Cardiac dysfunction
PPARα
−/−
↑Glucose uptake/utilization
↑[fructose], [ceramide], ROS
↓FAO, PDK4
↑Apoptosis, fibrosis
↓Cardiac function
G6PD‐deficient
C3H/HeJ
3 m
Normal
99
9 m
↑Oxidative stress
↓[Ca2+]i transport
↓Cardiac function over time
6 wks post‐TAC
↓Superoxide production
Tendency to develop LV dilation
100
17 wks post‐TAC (high fructose diet)
↓Aconitase
↑Pathological hypertrophy
↓Cardiac function
3 m post‐MI
↑Oxidative stress
↑LV dilation
↔Cardiac function, survival
I/R
↓Cellular glutathione (GST, GSH)
↑I/R injury
108
Cardiac‐specific overexpression of HK2
FVB/N
Baseline
↓Oxygen consumption
Normal
101
Isoproterenol infusion (2–3 mo old)
↑O‐GlcNAcylation
↓Cardiac hypertrophy
Cardiac‐specific knockout of OGT
C57BL/6
Baseline (4–5 wks)
↑COX IV, HK, PFK, GLUT1 mRNA levels
Perinatal death and heart failure
↑Apoptosis, fibrosis, ER stress
↑Cardiac hypertrophy
133
Cardiac‐specific het of OGT
C57BL/6
Baseline (2–4 m)
Progressive cardiomyopathy
Inducible cardiac‐specific knockout of OGT
C57BL/6
Baseline (<1 m)
↑GAPDH mRNA level
Normal
153, 158
Baseline (1–3 m)
↓Cardiac function over time
34
2 and 4 wks post‐TAC
↑TGFβ2 mRNA level
↓GATA4
↓Cardiac function
134
5 d post‐MI
↓PGC1‐α, PGC1‐β, CPT1, CPT2, MCAD, ATP‐5O, COXIV‐5B, GLUT1, GLUT4 mRNA levels
158
4 wks post‐MI
↑Apoptosis, fibrosis
↓Cardiac function
Ventricular‐specific knockout of HIF1α
Baseline
↓GLUT1, HK2, GPD1, GPAT, PPARγ mRNA levels
↑PPARα, PPARβ/δ mRNA levels
↑Mitochondrial‐related genes at mRNA levels
↑PGC1α, M‐CPT1, VDAC, SDHA
↑Repiratory function, DNA content, surface area of mitochondria
↓SERCA2, Ca2+ reuptake
↓ATP, phosphocreatine, lactate
↓Contractile function, mild hypovascularity
37, 38
14 to 18 d post‐TAC
↓TAG content
↓GAPDH, GPD1, GPAT activities
↓Apoptosis
↓Pathological hypertrophy
166
Ventricular‐specific knockout of Vhlh
Baseline
↑Glycolytic genes, GPD1, GPAT, PPARγ mRNA levels
↓PPARβ/δ mRNA level
↓Mitochondrial‐related genes at mRNA levels
↑HIF1α, PPARγ, FAT/CD36, GPAT
↓PGC1α, M‐CPT1, VDAC, SDHA
↓Repiratory function, DNA content, surface area of mitochondria
Cardiac hypertrophy
166
AOX indicates acyl‐CoA oxidase 1; AR, aldose reductase; ATP‐5O, ATP synthase subunit
5; COX 5B, cytochrome C oxidase subunit 5B; COX IV, cytochrome C oxidase subunit 4;
CPT1, carnitine palmitoyltransferase; FA, fatty acid; FAO, fatty acid oxidation; FAT/CD36,
fatty acid translocase/cluster of differentiation 36; G6PD, glucose 6‐phosphate dehydrogenase;
GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; GATA4, GATA binding protein 4; GLUT1,
glucose transporter type 1; GLUT4, glucose transporter type 4; GPAT, glycerol phosphate
acyltransferase; GPD1, glycerol 3‐phosphate dehydrogenase; HK2, hexokinase 2; I/R,
ischemia/reperfusion; LV, left ventricle; MCAD, medium chain acyl‐CoA dehydrogenase;
MI, myocardial infarction; OGT, O‐GlcNAc transferase; OXPHOS, oxidative phosphorylation;
PDK4, pyruvate dehydrogenase kinase 4; PFK‐2, phosphofructokinase‐2; PGC1‐β, PPARγ
coactivator 1 β; PGC1‐α, PPARγ coactivator 1 α; PPARα, peroxisome proliferator‐activated
receptor α; ROS, reactive oxygen species; SDH, sorbitol dehydrogenase; SDHA, succinate
dehydrogenase complex subunit A; SERCA2, sarcoplasmic/endoplasmic reticulum calcium
ATPase 2; TAC, thoracic aortic constriction; TAG, triglyceride; TGFβ2, transforming
growth factor β2; VDAC, voltage‐dependent anion channel.
Metabolic alterations in the heart for glycolysis, glucose oxidation, and FAO may
vary depending on the animal models, experimental settings, stage and severity of
cardiac hypertrophy and dysfunction, and different pathological stimuli. Although
evidence is mounting to support decreased FAO and increased glucose utilization, unchanged
or elevated FAO and unchanged or decreased glycolysis have also been found in hypertrophied
hearts.39 Angiotensin II induces cardiac hypertrophy and dysfunction, along with preservation
of FAO and glycolysis (slightly reduced, but not significant) and decreases in glucose
and lactate oxidation.40 Here, glycolysis rate may be modulated by the sustained/high
FAO rate through PFK1 inhibition41 and development of cardiac insulin resistance.
Angiotensin II has been found to induce insulin resistance,42 which may lead to impairment
of insulin‐dependent glucose uptake and glycolysis. Consistently, the defect in insulin‐induced
GLUT4 translocation may cause reduction of glycolysis in abdominal aortic constriction
hearts.39 Under insulin resistance, metabolic flexibility of utilizing FAs and glucose
is impaired. Therefore, the uncoordinated regulation of glucose oxidation, glycolysis,
and FAO may result in ATP deficit and development of heart failure.
Under physiological context, exercise may acutely suppress glycolysis and PFK activity,
which are then augmented in the recovery stage.26 It is implied that changes in glucose
utilization caused by regular exercise are important for maintaining mitochondrial
health and physiological cardiac growth, whereas a consistently high rate of glycolysis
induces pathological hypertrophy.26, 27
Glycolysis in the Ischemic and Failing Heart
Consequences of cardiac ischemia include poor oxygen supply and inadequate washout
of metabolic wastes.43 Lack of sufficient oxygen dampens cardiomyocyte capacity to
break down FAs, which, in turn, decreases the level of cellular citrate and indirectly
activates glucose uptake and glycolysis. As a result, glycolytic flux increases during
ischemia.43, 44, 45, 46, 47, 48 It has been shown that glucose uptake increases in
mild ischemia, whereas it may actually decrease in severe ischemia (near‐complete
blockage of coronary flow).43 When the coronary flow rate progressively reduces, modest
ischemia will become moderate and then severe. During this transition, glycolysis
produces ATP and maintains ionic homeostasis, providing a beneficial effect. However,
under severe ischemia, glycolysis may be more harmful than beneficial. Lack of washout
can lead to deleterious effects overshadowing the benefit of generation of anaerobic
ATP. Buildup of intracellular protons attributed to poor perfusion may inhibit glycolysis
in a feedback manner.43, 45 Further detrimental effects may include disruption of
ionic homeostasis by debilitating the Na+, Ca2+ efflux capacity of Na+/K+ ATPase and
Ca2+ ATPase,45 thereby impairing contractile function. In addition, pyruvate from
glycolysis forms lactate rather than entering pyruvate oxidation, which may lead to
an even higher level of lactate and lower rate of glucose oxidation. Collectively,
in a manner similar to that proposed in pathological cardiac hypertrophy, increased
glycolysis may be accompanied by uncoupling of glucose oxidation and elevation of
lactate and proton levels, which, together, contribute to myocardial injury.
Restoration after ischemia (ischemia/reperfusion; I/R) is the most effective approach
to mitigate cardiac damage and improve clinical outcomes.49 However, during reperfusion,
the glycolytic rate is still high without a parallel increase in glucose oxidation,
resulting in continuous reduction in cardiac efficiency.44, 45, 46, 47, 48 Moreover,
I/R restores extracellular pH and induces Na+/H+ and Na+/Ca2+ exchange, which may
adversely cause profound intracellular overload of Na+ and Ca2+. Therefore, ionic
imbalance is persistent during reperfusion that is considered a culprit for impaired
contractility.46 During reperfusion, the increase in FAO is accompanied by a decrease
in glucose oxidation, which causes further uncoupling between glucose oxidation and
glycolysis.50, 51
In congestive heart failure, the rate of FA utilization is induced whereas the glucose
utilization rate is suppressed.52, 53 The high level of plasma norepinephrine may
account for the elevated plasma free FAs through lipolysis and re‐esterification,
which, in turn, causes the decrement in glucose oxidation.54 Suppression of FAO may
represent a promising strategy to improve myocardial energy homeostasis.
In line with aforementioned animal studies, the uncoupling between glycolysis and
glucose oxidation has also been discovered in human failing hearts.55, 56 Furthermore,
high‐salt‐diet–induced heart failure with preserved ejection fraction shows a progressive
increase in glycolysis along with the development of hypertrophy and diastolic dysfunction
without changes in glucose oxidation. The mismatch between glycolysis and glucose
oxidation in the early stage may cause the development of heart failure with preserved
ejection fraction.56 Restoration of the coupling may be a potential therapeutic means
for treatment of heart failure.44, 45, 46, 56
It is worth noting that the reduction of FAO is not observed in onset of heart failure
with preserved ejection fraction, but only at the later stage.56 In support of this,
the rate of FA utilization, including FAO and lipid incorporation, is inversely correlated
with degree of cardiac dysfunction in chronically infarcted rat hearts.57 FAO and
glucose oxidation are unaltered in dogs with moderate coronary microembolization‐induced
heart failure.58 Furthermore, substrate utilization (eg, FAO) in patients with moderate
heart failure is similar to healthy controls.59 These data suggest a significant contribution
of the reduced FA utilization to the late stage of heart failure. The difference in
metabolic remodeling is likely determined by the type and severity of cardiac disease.
Further studies are warranted to dissect the underlying mechanisms for future clinical
applications.
Polyol Pathway
The polyol pathway consists of 2 enzymatic steps (Figure 3). The first reaction is
controlled by aldose reductase (AR) for reduction of glucose to sorbitol. The second
involves the action of sorbitol dehydrogenase to oxidize sorbitol to fructose. Under
euglycemic conditions, <3% of glucose is utilized by the polyol pathway, whereas >30%
of glucose is metabolized through this process in the intact rabbit lens under hyperglycemia.60,
61 In the heart, however, the metabolic rate through the polyol pathway remains undefined.
AR and sorbitol are known to maintain osmotic balance by regulating the volume and
intracellular environment of renal cells in response to alterations of external osmolality.62
Under hyperosmotic conditions, AR is induced in rat kidney mesangial cells, Chinese
hamster ovary cells,63 JS1 Schwann cells,64 and rat cardiomyocytes.65 Additionally,
overwhelming evidence suggests that AR may act as an antioxidant enzyme.66, 67 Under
high oxidative stress conditions, such as vascular inflammation,68, 69 ischemia,70
iron overload,71 and alcoholic liver disease,72 AR is elevated. At the functional
level, induction of AR displays cytoprotection against oxidative stress in the Chinese
hamster fibroblast cell line.73 Moreover, AR may regulate other glucose metabolic
pathways such as glycolysis and glucose oxidation.
Figure 3
The polyol pathway in the heart. In the polyol pathway, aldose reductase (AR) converts
glucose to sorbitol, which is subsequently oxidized to fructose by sorbitol dehydrogenase
(SDH). AR also acts as an antioxidant enzyme by catalyzing toxic aldehyde to nontoxic
alcohol. AGEs indicates advanced glycation end products; fructose 6‐P, fructose 6‐phosphate;
GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; GLUT, glucose transporter; GR, glutathione
reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; ROS, reactive oxygen
species.
Polyol Pathway in the Hypertrophic Heart
Limited studies have been directed to dissect the role of polyol pathway in development
of pathological cardiac hypertrophy. Recently, it has been reported that cardiac AR
expression28 and its products (fructose and sorbitol)74 are induced in hypertrophied
hearts and loss of AR leads to more‐profound hypertrophic growth and cardiac dysfunction.28
AR has been shown to hold the activity of detoxification of reactive aldehydes generated
by lipid peroxidation. AR deficiency in hypertrophied hearts may therefore impair
reactive aldehydes removal, resulting in elevation of aldehyde‐modified proteins such
as 4‐hydroxynonenal (HNE)‐protein and acrolein‐protein adducts. These modified proteins
participate in ATP production, protein folding, and autophagy.28 Autophagy in the
early stage of hypertrophic growth is adaptive; however, excessive autophagy may induce
maladaptive cardiac remodeling.75 Acute increase of AR in cardiac hypertrophy may
therefore serve as an adaptive defensive response to detoxify aldehydes and govern
autophagy.28 However, further studies are required for better understanding of the
mechanistic insights by which the polyol pathway regulates cardiac pathological remodeling.
Polyol Pathway in the Ischemic and Failing Heart
AR functions as an antioxidant enzyme in protecting hearts and arteries from the toxic
effects of lipid peroxidation products such as HNE and reactive aldehydes.61, 69,
76 Specifically, the generation of nitric oxide and activation of protein kinase C
are required for the action of AR in the late phase of ischemic preconditioning, which
consequently diminishes the injury caused by lipid peroxidation products.70 Reduction
of AR expression and activity in dogs’ failing hearts results in abnormal lipid‐peroxidation–derived
aldehyde metabolism and contributes to the excessive buildup of reactive aldehydes,
which may amplify chronic oxidative stress.77
Although ample findings support a beneficial effect of the polyol pathway during ischemia,
some studies have shown its contribution to the vulnerability of cardiovascular complications
in diabetes mellitus,78, 79, 80, 81, 82 ischemia,29, 83, 84, 85, 86, 87, 88 and aging.89
AR activation has been observed in ischemic hearts, which may exacerbate cardiac damage
after I/R and cause cardiac dysfunction in aging mice.29 Here, AR may drive the conversion
of glucose to fructose and diminish FA utilization.29 Additionally, AR may exacerbate
I/R injury by impairment of mitochondrial membrane function through inducing oxidative
stress (ie increase in malondialdehyde contents and decrease in mitochondrial antioxidant
manganese superoxide dismutase activity).87
Moreover, inhibition of AR shows cardioprotection in diabetic79, 80, 82 and ischemic
mice.83, 84, 85, 86, 87, 88, 90 The anti‐ischemic effects likely involve improving
cardiac energy metabolism83, 90 and contractile function,86, 88 suppressing oxidative
stress,84, 85, 88, 90, 91 and preserving mitochondrial function.87 Indeed, polyol
pathway inhibition is linked to a higher rate of glycolysis and more‐prominent ATP
generation.92 Elevated glycolysis and reduction of oxidative stress by AR inhibition
have been proposed to cause the reduction of NADH/NAD+ by attenuation of NAD+ use
through sorbitol dehydrogenase; hence, NAD+ is preserved for glyceraldehyde 3‐phosphate
dehydrogenase in glycolysis.84, 93 Additional evidence for the antioxidant effect
of AR inhibition is that it may reserve NADPH to fuel the glutathione reductase pathway.
Inhibition of AR alleviates I/R injury along with the decrease in reactive oxygen
species (ROS), malondialdehyde,91 and thiobarbituric acid reactive substances, the
by‐product of lipid peroxidation.85 Furthermore, AR inhibitor may attenuate elevation
of Na+ and Ca2+ during I/R. This effect has been explained, in part, by induction
of sodium and calcium efflux resulting from activation of Na+/K+ ATPase and Na+/Ca2+
exchanger by the AR inhibitor.94 Additionally, inhibition of AR restores the activity
of Ca2+ATPase by dampening tyrosine nitration and normalizing S‐glutathionylation
of this pump.88 Ectopic lipid accumulation in the heart may contribute to the pathogenesis
of cardiovascular disease.95, 96, 97 AR promotes lipid accumulation in the heart by
competing with histone deacetylase 3 for corepressor complex interaction, resulting
in free histone deacetylase 3 for degradation. This action leads to downregulation
of the peroxisome proliferator‐activated receptor γ and retinoic acid receptor pathways
and, consequently, lipid accumulation.98
The role of the polyol pathway on redox stress in diabetes mellitus is emerging.99
A reduced content of NADPH has been found in diabetic lung100 and pancreas.101 The
usage of NAPDH by AR may reduce NAPDH availability for glutathione reductase to maintain
reduced glutathione and may induce superoxide generation. Moreover, NADH level is
elevated in chronic hyperglycemia that involves reduced glycolysis,92 impairment of
mitochondrial function, and augmented ROS generation.102 This increase of NADH may
be associated with the polyol pathway. The usage of NAD+ by sorbitol dehydrogenase,
the second step in the polyol pathway, can reduce the content of NAD+ for glycolysis
and produce NADH. In addition, fructose produced by the polyol pathway is converted
into fructose 3‐phosphate and leads to generation of 3‐deoxyglucosone, a precursor
for advance glycation end product formation. AR may therefore catalyze advance glycation
end product production and induce oxidative stress. Excessive accumulation of advance
glycation end products contributes to the pathogenesis of diabetic complications.103,
104
It is worth mentioning that the osmotic consequence of activated polyol pathway in
diabetes mellitus is one of the potential pathological mechanisms. Accumulation of
sorbitol causes hyperosmotic stress, which is associated with development of diabetic
cataract,105 reduced Na+/K+ ATPase activity, elevated oxidative stress,106 and ATP
deficit.107 In cultured rat cardiomyocytes, AR not only contributes to the depletion
of glutathione content, but also hyperosmotic stress‐induced apoptosis.65 Taken together,
it is possible that the role of the polyol pathway or AR in the heart depends on the
context of pathological cardiac disease. More work remains to be done to understand
how the polyol pathway senses the signals to defend or exacerbate cardiac injury under
different pathological contexts.
Pentose Phosphate Pathway
There are 2 branches in the PPP: oxidative and nonoxidative. The oxidative PPP generates
NAPDH and ribulose 5‐phosphate (Figure 4). On the other hand, the nonoxidative branch
metabolizes ribulose 5‐phosphate to 5‐carbon sugars for nucleotide biosynthesis or
generation of intermediates for the glycolytic pathway (ie, glyceraldehyde 3‐phosphate
and fructose 6‐phosphate). The nonoxidative reactions are reversible, which may regenerate
ribulose 5‐phosphate from glycolytic intermediates. The oxidative PPP is a critical
source of cytosolic NADPH that maintains reduced glutathione levels.30 Moreover, NAPDH
contributes to the generation of cytosolic ROS through activation of NADPH oxidase
and nitric oxide synthase. Thus, the PPP may play a dual role in the regulation of
redox balance.6
Figure 4
The pentose phosphate pathway in the heart. The oxidative phase of the pentose phosphate
pathway (PPP) generates NADPH and ribulose 5‐phoshpate (ribulose 5‐P), which are mainly
used for anabolism. The nonoxidative phase of PPP stimulates the interconversion of
5‐carbon sugars with a series of reversible reactions. Whereas acute activation of
the PPP confers cardioprotection against oxidative stress, persistent upregulation
of the PPP may exacerbate oxidative damage and contribute to cardiomyopathies. 6GPD
indicates 6‐phosphogluconate dehydrogenase; fructose 6‐P, fructose 6‐phosphate; G6PD,
glucose 6‐phosphate dehydrogenase; GLUT, glucose transporter; glyceraldehyde 3‐P,
glyceraldehyde 3‐phosphate; HK, hexokinase; ribose 5‐P, ribose 5‐phosphate; xylulose
5‐P, xylulose 5‐phosphate.
PPP in the Hypertrophic Heart
The role of the PPP in maintenance of cytosolic redox homeostasis has been reported
from studies on glucose 6‐phosphate dehydrogenase (G6PD), the rate‐limiting enzyme
of the PPP. In response to cellular oxidative stress, G6PD activity is rapidly increased
with corresponding translocation from the cytosol to the cell‐surface membrane.30
At both in vitro and in vivo levels, G6PD shows a cardioprotective effect against
free radical injury whereas depletion of G6PD causes adversity on cardiac contraction.30
In addition, G6PD‐deficient mice display progressive pathological structural modeling
and develop moderate hypertrophy at 9 months of age.30 Cardiac oxidative stress in
these animals is augmented in response to MI or pressure overload.31 Glucose phosphorylation
by hexokinase is the first step to initiate glucose utilization. Overexpression of
hexokinase 2 shows an antihypertrophic effect in both phenylephrine‐triggered hypertrophic
cardiomyocytes and isoproterenol‐induced cardiac hypertrophy in mice.33 Importantly,
the beneficial effect of hexokinase 2 is associated with an elevated G6PD activity,
leading to enhanced glucose utilization through the PPP and attenuated ROS accumulation.33
Taken together, increase in G6PD under various pathological conditions may serve as
a defensive mechanism to protect cardiac myocytes against injury.
PPP in the Ischemic and Failing Heart
A detrimental effect of the oxidative PPP has been found in cardiac I/R.108 During
acute I/R, the oxidative PPP‐derived NAPDH is mostly metabolized by NAPDH oxidase
and nitric oxide synthase. Inhibition of the oxidative PPP as well as NAPDH oxidase/nitric
oxide synthase is cardioprotective against I/R‐induced creatinine kinase release (an
index of cardiac injury). Furthermore, an increase in G6PD expression and activity
has been observed in both human and canine heart failure.109, 110 Importantly, the
PPP‐derived NAPDH is also elevated and fuels superoxide production in failing hearts.
Collectively, these observations strongly suggest that the increased availability
of NAPDH, presumably through the oxidative PPP in failing hearts, may have a more‐dominant
effect on stimulating superoxide generation compared with its antioxidant role. Under
the condition of severe heart failure, the glycolytic pathway is depressed.111, 112
It is possible that a larger fraction of glucose entering cardiomyocytes triggers
upregulation of the PPP. Interestingly, elevation of blood glucose after meals rapidly
boosts the generation of ROS in failing hearts, but does not have an effect in normal
hearts. This repeated physiological effect likely adds more oxidative stress to the
failing heart.113 Indeed, inhibition of the oxidative PPP during acute hyperglycemia
enhances cardiac glucose oxidation, oxygen consumption, and cardiac work and prevents
oxidative stress in failing hearts.113 This inhibition may, however, be partial given
that complete inhibition of oxidative PPP may cause an adverse effect, as observed
in isolated adult cardiomyocytes.30 The partial inhibition is sufficient to maintain
a proper balance of reduced glutathione for the antioxidant system while blunting
the harmful, excessive level of NAPDH. It is, however, not clear whether sustained
suppression of the oxidative PPP at the early stage of heart failure development would
mitigate oxidative stress and dampen disease progression. It seems that in the onset
of cardiac remodeling, the PPP acts as an adaptive response to accommodate cardiac
stress by maintaining redox homeostasis.32 However, under persistent stress, the PPP
may contribute to the pathogenesis of heart failure. The intracellular pathways mediating
PPP actions remain to be fully characterized.
The important role of the PPP in maintaining proper intracellular redox states has
also been revealed in cardiac progenitor cells (CPCs).114 The activities of key enzymes
of the PPP (G6PD and transketolase) are reduced in CPCs of diabetic mice, leading
to accumulation of glucose metabolic intermediates and execution of apoptosis. Importantly,
upregulation of the PPP by benfotiamine treatment in diabetic mice restores G6PD and
transketolase activities, decreases ROS and advance glycation end product accumulation,
and prevents CPCs from cell demise. Consequently, development of cardiomyopathy and
postischemic heart failure in diabetic mice is attenuated.114 The beneficial effect
of the PPP in progression of heart failure has also been shown in Dahl salt‐sensitive
rats.115 Indeed, dichloroacetate treatment induces the PPP, which is involved in prevention
of left ventricular hypertrophy and heart failure.
At the mechanistic level, decrease of the PPP in CPCs may be attributed to upregulation
of glycolysis and glycerolipid biosynthesis.116 Salabei et al show that 6‐phosphofructo‐2‐kinase/fructose
2,6‐P2 bisphosphatase 3, an isoform of PFK2, is significantly elevated in diabetic
CPCs, which may promote usage of 3‐carbon intermediates of glycolysis for glycerolipid
production and consequently suppress glucose utilized for the PPP. This metabolic
imbalance may lead to impairments in mitochondrial function and CPC proliferation.
In agreement, the metabolite profiles of ex vivo rodent hearts perfused with glucose117
or PFK2 mutant‐expressing cardiomyocytes118 show that PFK coordinately regulates glycolysis
and other ancillary glucose metabolic pathways, including the PPP, the HBP, glycerolipid
biosynthesis, and the polyol pathway. Activation of PFK causes a disproportionate
distribution of glucose flux by directly limiting intermediates of glycolysis for
ancillary glucose metabolic pathways and indirectly regulating the cataplerotic activity
of mitochondria.118
Along these lines, decrease in the PPP may also limit proliferation of fetal cardiomyocytes
under diabetic conditions. Ribulose 5‐phosphate is an important intermediate of the
PPP pathway,119 which can be used for glucose production, glycolysis, pyrimidine nucleotide
synthesis, purine nucleotide synthesis, and ATP generation. Recently, it has been
shown that cardiomyocyte maturation is induced by nucleotide deprivation, not by cell‐cycle
blockage.120 Importantly, the role of nucleotide biosynthesis by the PPP is indicated
as a primary determinant of the promitotic effect of glucose. These findings may provide
certain mechanistic explanations for congenital heart disease in gestational diabetes
mellitus, in which the high blood glucose level may suppress fetal cardiomyocytes
proliferation. Therefore, targeting the PPP to control the proliferation of CPCs and
cardiomyocytes may represent a promising approach for cardiac regeneration and treatment
of diabetes mellitus–related cardiac disease.
Hexosamine Biosynthetic Pathway
At baseline, 2% to 5% of glucose is metabolized by the HBP, which has been found in
adipocytes and skeletal muscle.121, 122, 123 This contribution can be significantly
larger under stress conditions.124 The HBP is regulated by both nutrient inputs (glucose
and glucosamine) and the rate‐limiting enzyme, glutamine:fructose 6‐phosphate amidotransferase
(GFAT; Figure 5). GFAT converts fructose 6‐phosphate to glucosamine 6‐phosphate and
eventually generates the final product, uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc).
UDP‐GlcNAc serves as a substrate for the synthesis of proteoglycan, hyaluronan, glycolipid,
glycosylphosphatidylinositol anchor, and N‐glycan. Additionally, UDP‐GlcNAc is used
for O‐GlcNAcylation, a prominent posttranslational modification of O‐linked β‐N‐acetylglucosamine
(O‐GlcNAc).125, 126, 127, 128 The 2 key enzymes of O‐GlcNAcylation are O‐GlcNAc transferase
(OGT) and O‐GlcNAcase, which add the GlcNAc moiety donated from UDP‐GlcNAc to, and
remove from, target proteins at the Ser/Thr amino acid residues, respectively. This
dynamic process plays a critical role in sensing cellular stressors, cell‐cycle alterations,
and nutrient levels, which has been implicated in the pathophysiology of various heart
diseases.129, 130, 131
Figure 5
The hexosamine biosynthetic pathway (HBP) in the heart. The rate‐limiting enzyme of
the HBP, GFAT, converts fructose 6‐P and glutamine to glucosamine 6‐phosphate, which
is used to generate the final product, UDP‐GlcNAc. UDP‐GlcNAc is a substrate for various
biosynthetic pathways, including glycan synthesis, glycerolipid production, etc. UDP‐GlcNAc
is also used for a prominent posttranslational protein modification on Ser/Thr sites
by O‐GlcNAc transferase (OGT), which is counteracted by O‐GlcNAcase (OGA) to catalyze
the removal of O‐GlcNAc. GFAT indicates glutamine:fructose 6‐phosphate amidotransferase;
GLUT, glucose transporter; HK, hexokinase; UDP‐GlcNAc, uridine diphosphate N‐acetylglucosamine.
HBP and O‐GlcNAcylation in the Hypertrophic Heart
Previous studies have shown that the HBP and O‐GlcNAcylation are activated during
cardiac hypertrophy development. Indeed, pressure overload induces mRNA expression
of GFAT2 and OGT and increases cardiac UDP‐GlcNAc levels.132, 133 Correspondingly,
O‐GlcNAc posttranslational modification on cardiac proteins is augmented.133, 134,
135, 136 Moreover, the increase in O‐GlcNAcylation has been revealed in hearts of
hypertensive rats and aortic stenosis patients.133 Similarly, cardiomyocytes treated
with hypertrophic stimuli (ie, phenylephrine, angiotensin II) show increases in O‐GlcNAc
levels whereas HBP inhibition causes a decrease in O‐GlcNAc levels and counteracts
the prohypertrophic effect.135, 137 These findings suggest that O‐GlcNAcylation plays
an important role in pathological cardiac hypertrophy, and inhibition of O‐GlcNAcylation
blunts hypertrophy progression. However, long‐term reduction of O‐GlcNAc levels is
detrimental and causes cardiomyopathy.34, 36
Furthermore, diabetes mellitus is associated with cardiac hypertrophy and elevation
of O‐GlcNAcylation.137, 138, 139, 140 The increase of O‐GlcNAcylation is accompanied
by impaired cardiac hypertrophy in db/db diabetic hearts along with augmentation of
B‐cell lymphoma 2 (Bcl‐2)‐induced cardiomyocyte death, thereby accelerating the progression
to heart failure.137 In both high‐glucose–treated cardiac myocytes and hypertrophic
myocardium of streptozotocin‐induced diabetic rats, O‐GlcNAc levels, extracellular
signal–regulated kinase 1 and 2 (ERK1/2) activity, but not p38 mitogen‐activated protein
kinase or c‐Jun N‐terminal kinase (JNK) activity, and cyclin D2 expression are upregulated.139
Accordingly, inhibition of O‐GlcNAcylation blocks activation of ERK1/2, hypertrophic
growth, and cyclin D2 expression.139 ERK1/2 promotes compensative cardiac hypertrophy,
whereas p38 and JNK are involved in development of cardiomyopathy.141 In this context,
O‐GlcNAcylation may contribute to an adaptive form of cardiac hypertrophic growth.
The role of O‐GlcNAcylation in cardiac hypertrophy is complex and depends on the type
of hypertrophic growth.33 It is well known that calcineurin‐NFAT (nuclear factor of
activated T cells) signaling governs cardiac hypertrophy in response to pressure overload.142
O‐GlcNAc modification on NFAT is required for its translocation from the cytosol to
the nucleus, where NFAT stimulates the transcription of various hypertrophic genes.
In other words, O‐GlcNAc may contribute to cardiac hypertrophy through NFAT activation.143
Consistently, inhibition of O‐GlcNAcylation dampens NFAT‐induced cardiac hypertrophic
growth. More recently, the antihypertrophic action of AMP‐activated protein kinase
has been firmly associated with reduction of O‐GlcNAcylation.144 Importantly, O‐GlcNAcylation
of troponin T is one of the downstream targets of AMP‐activated protein kinase in
cardiac hypertrophic growth.144 There are several additional O‐GlcNAcylated proteins
from cardiac myofilaments, including cardiac myosin heavy chain, α‐sarcomeric actin,
myosin light chain 1 and 2, and troponin I.145 These key contractile proteins are
O‐GlcNAcylated at phosphorylated or nonphosphorylated sites. For example, myosin light
chain 1 is O‐GlcNAcylated at Thr 93/Thr 164, which are different from phosphorylation
sites at Thr 69 and Ser 200.145, 146 However, the O‐GlcNAc residues in cardiac troponin
I and myosin light chain 2 lie on the phosphorylation sites Ser 150 and Ser 15, respectively.145
At the functional level, O‐GlcNAcylation of key contractile proteins may inhibit protein‐protein
interactions, resulting in reduction of calcium sensitivity, and thereby modulating
contractile function.147
Under the physiological context, decreases in HBP and O‐GlcNAcylation have been shown
in hearts of swim‐trained mice.148 Additionally, in treadmill running mice, cytosolic
O‐GlcNAcylated proteins are decreased after 15 minutes of exercise, whereas there
is no change of O‐GlcNAcylation 30 minutes later.149 Mechanistically, this acute response
leads to removal of O‐GlcNAc groups from OGT, resulting in dissociation of OGT and
histone deacetylases from the repressor element 1–silencing transcription factor chromatin
repressor and triggering physiological hypertrophic growth.149 Interestingly, swim
training normalizes elevated O‐GlcNAcylation in hearts of streptozotocin‐induced diabetic
mice by increasing O‐GlcNAcase expression and activity; however, there is no change
in OGT.150 Collectively, these findings highlight the role of O‐GlcNAcylation in physiological
cardiac hypertrophic growth.
HBP and O‐GlcNAcylation in the Ischemic and Failing Heart
In response to various cellular stresses, the HBP and O‐GlcNAcylation increase rapidly.151,
152, 153 Previous studies have shown that elevated O‐GlcNAcylation confers strong
cardioprotection in I/R.75, 154, 155, 156, 157, 158, 159 This is partly explained
by increasing O‐GlcNAcylated voltage‐dependent anion channels and reducing sensitivity
to mitochondrial permeability transition pore opening, thereby increasing mitochondrial
tolerance to oxidative stress.154, 160 In addition, induction of the HBP and O‐GlcNAcylation
by glucosamine promotes mitochondrial Bcl‐2 translocation, which is associated with
restoration of mitochondrial membrane potential and cardioprotection.155, 157 Moreover,
protection of increased O‐GlcNAcylation has been proposed to attribute to depletion
of the calcium‐induced stress response.158, 159 Recently, elevated O‐GlcNAcylation
and OGT expression along with reduction of OGA have been reported in infarction‐induced
heart failure in mice.35 Cardiomyocyte‐specific deletion of OGT causes significant
reduction in O‐GlcNAcylation, which provokes heart failure after MI and impairs cardiac
compensatory potential during heart failure development.35 Together, mounting evidence
suggests that acute increase of O‐GlcNAcylation is beneficial in the heart against
various stressors.
As a metabolic and stress sensor, O‐GlcNAcylation is altered in several chronic disease
conditions161 including heart disease.140, 153, 162 Induction of O‐GlcNAcylation has
been observed in hypertensive hearts,133, 163 diabetic hearts,164, 165 chronically
hypertrophied hearts, and failing hearts.133 Studies have shown that this increase
may contribute to contractile and mitochondrial dysfunction.162 Consistently, suppression
of O‐GlcNAcylation by overexpression of O‐GlcNAcase normalizes cardiac O‐GlcNAcylation
levels and improves calcium handling and cardiac contractility in the diabetic heart.166
Thus, it is speculated that the acute increase in O‐GlcNAcylation is an adaptive response
to protect the heart from injury, whereas prolonged, persistent activation is maladaptive
and contributes to cardiac dysfunction.
Emerging evidence has shed light on the upstream regulators of the HBP. We have shown
that GFAT1 is a direct target of X‐box binding protein 1 (XBP1s), a key transcriptional
factor of the unfolded protein response (UPR).124 Consistently, overexpression of
XBP1s in cardiomyocytes promotes HBP activity, resulting in elevation of UDP‐GlcNAc
levels and O‐GlcNAcylation. Notably, I/R activates XBP1s, which couples the UPR to
the HBP to protect the heart from reperfusion injury.124 More recently, another UPR
effector, activating transcription factor 4 (ATF4), has been demonstrated as a direct
regulator of GFAT1 expression.167 Deprivation of amino acids or glucose activates
the general control nonderepressible 2/eukaryotic initiation factor 2 alpha/ATF4 pathway
and leads to increases in GFAT1 and O‐GlcNAcylation.167 Taken together, the HBP and
cellular O‐GlcNAcylation may serve as a buffering mechanism for the UPR to accommodate
fluctuations in the cell in response to intra‐ or extracellular cues.
Other Glucose Metabolic Pathways
Glycerolipid Synthetic Pathway
Fructose 1,6‐bisphosphate, an intermediate of glycolysis, can be converted to glyceraldehyde
3‐phosphate and dihydroxyacetone phosphate. Dihydroxyacetone phosphate may then be
reduced to glycerol 3‐phosphate (glycerol 3‐P) by glycerol 3‐P dehydrogenase. Glycerol
3‐P is derived from not only glucose through glycolysis, but also glycerol through
the action of glycerol kinase, which serves as a substrate for acylation by glycerol
3‐P acyltransferase, the first step of the glycerolipid synthetic pathway (GLP).
Although little is known about the role of the GLP in cardiomyopathy, the activities
of glycerol 3‐P dehydrogenase and glycerol 3‐P acyltransferase, 2 crucial enzymes
of the GLP, are elevated in hypertrophied hearts.37 Studies show that the GLP is,
at least in part, associated with regulation of glycolysis by hypoxia‐inducible factor
1 alpha (HIF‐1α)37, 38 and PFK.116 Emerging evidence indicates that HIF1α and peroxisome
proliferator‐activated receptor γ are elevated in pathological cardiac hypertrophy.
Interestingly, induction of peroxisome proliferator‐activated receptor γ expression
by hypertrophy is HIF1α dependent, which subsequently induces glycerol 3‐P acyltransferase.
Therefore, hypertrophy‐activated HIF1α triggers the synthesis of lipids by coregulation
of glycolysis and GLP. At the functional level, HIF1α‐mediated cardiac lipid accumulation
leads to cell death through the HIF1α/peroxisome proliferator‐activated receptor γ/octamer
1/growth arrest and DNA‐damage‐inducible α axis. Suppression of HIF1α therefore protects
the heart from hypertrophy‐induced cardiac dysfunction. This cardioprotection may
be attributed to, at least partly, the increases of cAMP response element‐binding
protein activity and sarco/ER Ca2+‐ATPase 2A expression.37 Additionally, activation
of PFK in diabetic CPCs induces glycolysis and promotes the conversion of the 3‐carbon
intermediates of glycolysis to GLP. As a consequence, the GLP may initiate an adipogenic
program in CPCs and contribute to lipid accumulation.116 In cardiomyocytes, low glycolytic
activity may reduce glycerophospholipid synthesis at the glycerol 3‐P dehydrogenase
1–committed step. In contrast, high glycolytic activity could promote phosphatidylethanolamine
synthesis while attenuating glucose‐derived carbon incorporation into the FA chains
of phosphatidylinositol and triacylglycerols.118 Taken together, these findings suggest
that there is a concerted regulation of glycolysis and GLP in response to stress‐induced
pathological hypertrophy. Further work is needed to dissect the direct link of GLP
with pathological cardiac remodeling.
Serine Biosynthetic Pathway
Serine biosynthesis is another ancillary glucose metabolic pathway to use glyceraldehyde
3‐P to generate serine in 3 steps by phosphoglycerate dehydrogenase, phosphoserine
aminotransferase 1, and phosphoserine phosphatase. Serine can be used to synthesize
amino acids glycine and cysteine, which are biosynthetic precursors of glutathione,
purine, and porphyrin. Serine may also constitute components of sphingolipids and
phospholipids. In addition, serine provides the 1‐carbon units to the 1‐carbon metabolism
pathway for purine, thymidine, methionine, and 5‐adenosylmethionine syntheses.168
Because of the requirement of serine in the synthesis of variously important molecules,
it is proposed as a central metabolic regulator of cell function, growth, and survival.169,
170 There are extensive studies on the role of serine biosynthesis in cancer168, 171,
172 whereas the importance in cardiac disease is poorly understood. Recently, activation
of serine and the 1‐carbon metabolism pathway induced by CnAβ1, a calcineurin isoform,
shows a protective effect in the heart under pressure overload.173 Induction of this
pathway leads to increased ATP synthesis and reduced glutathione levels, improved
cardiac contraction, and cardioprotection against oxidative injury. Further work is
warranted to delineate the role of serine biosynthesis in cardiac physiology and pathophysiology.
Glycogen Metabolic Pathways
Glucose can be converted to glycogen, a multibranched polymer of glucose, for storage
through the glycogen synthesis pathway. Cardiac glycogen serves as a significant source
of glucose to support high energy demand not only in the normal heart, but also in
the hypertrophied heart during normal aerobic perfusion174, 175 or under low‐flow
ischemia.176, 177 In the hypertrophied heart, glycolysis using glycogen‐derived glucose
is not altered compared with that in the normal heart whereas glycolysis with exogenous
glucose is increased.175 Also, myocardial glycogen turnover occurs in both normal
and hypertrophied hearts. During mild/moderate low‐flow ischemia, rates of glycolysis
as well as glucose oxidation are not different in the hypertrophied heart compare
with those in the normal heart.176 The contribution of glycogen metabolism in the
hypertrophied heart during normal aerobic flow or mild/moderate low‐flow ischemia
is similar to those in the normal heart. However, during severe low‐flow ischemia,
rates of glycolysis from both exogenous glucose and glycogen are augmented in the
hypertrophied heart, along with the increase in glycogen turnover.
In ischemic preconditioning, reduced glycogenolysis and cardiac glycogen content may
decrease glucose availability for glycolysis, lower acid production, and protect the
heart from ischemic injury.178 In I/R, elevation in glycogen synthesis lowers the
source of glucose for glycolysis, decreases acid generation, and prevents Ca2+ overload.179
In rats under fasting conditions, cardiac glycogen content is elevated, which protects
the heart from ischemic damage. The increased glycogen utilization may serve as a
critical source of ATP to maintain calcium homeostasis. On the other hand, fed rats
similarly show elevation in cardiac glycogen content. However, the increase of circulating
insulin limits glycogen utilization, which leads to an increase in lactate production
and more‐pronounced cardiac injury by ischemia.180 Taken together, understanding of
the fundamental bases for glycogen homeostasis in cardiac pathophysiology is essential
to harness the knowledge for therapeutic gain.
Pharmacological Agents to Modulate Metabolic Remodeling
There are a number of potential metabolic targets for treatment of heart diseases.
The central goals of metabolic therapies are maintenance of flexibility in substrate
use and the capacity of cardiac oxidative metabolism, which may, in turn, promote
myocardial energy efficiency and improve cardiac function.181 FAO is a major contributor
to energy production in the normal heart; however, FAO is less energy efficient than
glucose oxidation because of its higher oxygen consumption. Therefore, optimizing
cardiac energy metabolism by inhibiting FAO and inducing glucose oxidation may be
a potential approach to treat heart failure.45, 182
Inhibiting FA Uptake
Carnitine palmitoyltransferase 1 (CPT1) is a key enzyme for FA uptake into mitochondria.
Direct modulation of FAO using carnitine palmitoyltransferase 1 inhibitors (eg, etomoxir
and perhexiline) shows beneficial effects in treatment of heart failure. Etomoxir
inhibits carnitine palmitoyltransferase 1 and suppresses FAO, along with augmented
glucose oxidation, resulting in cardioprotection from ischemia.183 Treatment of etomoxir
also improves myocardial performance of hypertrophied hearts following pressure overload184
and slows the progression from compensatory to decompensated cardiac hypertrophy,
in part, by inducing sarcoplasmic reticulum Ca2+ transport.185 Both etomoxir and perhexiline
show beneficial effects on the improvement of left ventricular ejection fraction of
patients with chronic heart failure.186, 187 However, use of these agents for heart
failure is limited (perhexiline) or even terminated (etomoxir) because of hepatotoxic
side effects.
Suppressing FA β‐oxidation
Trimetazidine suppresses the rate of FAO by inhibiting 3 ketotacyl‐CoA thiolase, the
last enzyme in FAO, concomitant with increased glucose oxidation. Clinically, trimetazidine
is used as an antianginal agent in the treatment for stable angina. It improves left
ventricular ejection fraction in patients with either ischemic cardiomyopathy188 or
idiopathic dilated cardiomyopathy.189 Especially, idiopathic dilated cardiomyopathy
treatment with trimetazidine shows reduced FAO as well as increased insulin sensitivity.
In addition, the improvement of ejection fraction by trimetazidine is more dramatic
when used together with β‐blockers, suggesting an additive effect of trimetazidine
and β‐adrenoceptor antagonism.189
Reducing Circulating FA
Glucose‐insulin‐potassium (GIK) increases glycolysis, reduces levels of circulating
free FA, and hence decreases FAO. GIK had beneficial effects in patients with MI,
shown by reduction of infarct size and mortality.190, 191, 192, 193, 194 However,
effects of GIK are not always consistent. Some clinical studies have reported that
GIK did not improve survival and decrease cardiac events in patients with acute MI.195,
196 Clinical use of GIK remains to be fully validated.
Increasing Glucose Oxidation
Activation of glucose oxidation is an effective way to provide a more energy‐efficient
substrate, which may show beneficial effects on improving cardiac function. Dichloroacetate
(DCA) enhances glucose oxidation by activating the pyruvate dehydrogenase complex,
which is associated with improvement of coupling between glycolysis and glucose oxidation
in the heart after ischemia197 or pressure overload.198 Likewise, DCA promotes myocardial
efficiency in patients with coronary artery disease.199 The beneficial effects of
DCA in high‐salt‐diet–induced congestive heart failure in Dahl salt‐sensitive rats
are associated with increases in glucose uptake, cardiac energy reserve, and the PPP
and the decrease in oxidative stress.115 However, DCA does not show its protective
effects in patients with congestive heart failure.200 In diabetic rat hearts, although
DCA treatment during reperfusion significantly augments glucose oxidation, DCA has
no effect on functional recovery from ischemic injury. Glucose oxidation may not be
a key factor in governing the ability of diabetic rat hearts to recover from I/R.201
Conclusions and Future Perspectives
Numerous studies have firmly established that heart failure is associated with profound
metabolic remodeling. Multiple layers of crosstalk exist among individual glucose
metabolic pathways to regulate substrate availability and ATP production. The increase
in glucose metabolism in onset of heart disease is associated with an adaptive mechanism
to protect the heart from injury. Chronic activation, however, may lead to decompensation
and heart failure progression. Metabolic remodeling plays an essential role in regulating
not only nutrient utilization, but also ionic and redox homeostasis, UPR, and autophagy,
thereby affecting cardiac contractile function. A better and more‐thorough understanding
of the mechanisms of action and regulation may pave a new way for therapeutic discoveries
to tackle heart failure.
Sources of Funding
This work was supported by grants from American Heart Association (14SDG18440002,
17IRG33460191), American Diabetes Association (1‐17‐IBS‐120), and NIH (HL137723) (to
Wang).
Disclosures
None.