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Basic Science for Clinicians
AMP-Activated Protein Kinase Conducts the Ischemic Stress
Response Orchestra
Lawrence H. Young, MD
T
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he heart is subjected to physiological stress in normal
individuals during exercise and to pathological stress in
patients with ischemic disease, ventricular pressure, or volume overload. How the heart responds depends on the type,
intensity, and duration of the stress. Just as extrinsic physiological reflexes are activated when cardiac output falls,
internal molecular sensors respond to changes in physiological parameters within cardiac cells. These specialized molecules sense perturbations in oxygen tension, cell stretch, pH,
membrane potential, oxidative state, and intracellular energy
stores, with the latter particularly pertinent to this discussion.
The present article will focus on the AMP-activated protein
kinase (AMPK), a molecular stress response pathway that is
activated by increases in the intracellular concentration of
AMP. AMP is not to be confused with cAMP, a molecular
signal produced during stress by catecholamine-induced
␤-adrenergic stimulation. The AMPK pathway has received a
great deal of attention because of its potential importance in
the ischemic heart,1,2 diabetes,3 and cancer.4 Several recent
reviews have summarized scientific discoveries related to
AMPK and can provide the interested reader with additional
insights into the field.2,5–7 The present article will strive to
provide a perspective that is accessible to the clinician with
an interest in contemporary basic science research. It is hoped
that the reader will develop an understanding of how AMPK
functions in the heart to orchestrate the cellular response to
ischemic stress.
the cell is under metabolic stress (Figure 1). Normally, AMP
is present in substantially lower concentrations than ATP.9
Even a small amount of ATP breakdown significantly increases the concentration of AMP. Thus, AMP is a very
sensitive and early indicator of compromised energy
availability.8
How does AMP work as a molecular signal? AMP directly
regulates a limited number of enzymes that are involved in
metabolic pathways responsible for cellular energy generation (Figure 1). For instance, AMP activates glycogen phosphorylase, which releases stored glucose from glycogen, an
important source of energy when fuel oxidation is impaired
during ischemia. AMP similarly activates the enzyme
phosphofructokinase-1 (PFK-1). PFK-1 acts as a metabolic
gatekeeper, regulating the entry of glucose into glycolysis.
However, the molecular signaling role of AMP is dramatically extended by activation of the AMPK pathway. Because
many more proteins are regulated by AMPK than contain
specialized AMP-binding sites, the ability of AMP to signal
energy compromise is greatly enhanced.
AMPK is a protein kinase that has taken center stage in
metabolic regulation over the last decade. Protein kinases are
specialized enzymes that transfer phosphate groups from
ATP to amino acids on specific target proteins. The phosphorylation of even a single amino acid can induce conformational changes in enzymes, ion channels, and regulatory
and structural proteins that alter their function. AMPK was
first identified 20 years ago as a protein kinase that was
responsive to changes in the concentration of AMP and modulated the activity of the enzymes acetyl-CoA carboxylase and
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.10 Phosphorylation of acetyl-CoA carboxylase inhibits its action to synthesize malonyl-CoA, a small molecule
that functions as an activator of fatty acid synthesis in the
liver and an inhibitor of fatty acid oxidation in the heart.11
Phosphorylation of HMG-CoA reductase inhibits cholesterol
biosynthesis.10 The physiological significance of this action is
not fully understood, but AMPK might contribute to the drop
in cholesterol levels observed in patients during acute coronary syndromes. It is interesting that statins also activate
AMPK, which might augment their direct action to inhibit
HMG-CoA reductase and lower cholesterol levels.12
AMP and Cellular Energy Stress
Cells have evolved elaborate mechanisms to protect themselves against changes in their environment. In the heart, one
of the most important forms of cellular stress is energy
depletion from ischemia. ATP is the primary energy source
for contractile proteins, ion pumps, and many enzymes.
Normally, energy production and utilization are tightly coupled in the heart. When ATP generation from substrate
metabolism fails to keep pace with ATP utilization, the
intracellular concentration of ADP increases. Two molecules
of ADP are converted to 1 molecule each of ATP and AMP
through the action of the enzyme adenylate kinase.8 This
reaction not only helps to regenerate ATP as an energy source
but also forms AMP. AMP serves as an internal signal that
From the Departments of Internal Medicine (Section of Cardiovascular Medicine) and Cellular and Molecular Physiology, Yale University School of
Medicine, New Haven, Conn.
This article is the fifth in a series of on the topic of “Targeting Metabolism as a Therapeutic Approach for Cardiovascular Diseases.”
Correspondence to Lawrence H. Young, MD, 333 Cedar St, New Haven, CT 06520. E-mail [email protected]
(Circulation. 2008;117:832-840.)
© 2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.107.713115
832
Young
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Figure 1. AMP as a molecular signal during ischemia. Alterations in myocardial energy production during ischemia lead to
an imbalance in ATP generation and utilization. Thus, ischemia
leads to the formation of AMP, which signals that the cell is
developing metabolic compromise. An increase in the concentration of AMP directly activates specific molecules involved in
energy-generating metabolic pathways (glycogen breakdown
and glycolysis) and AMPK. Activated AMPK regulates a wide
range of molecular pathways, which might be considered a
stress response orchestra.
AMPK has come to be known as a molecular “fuel gauge”
or “metabolic sensor.”13 It phosphorylates a variety of proteins including metabolic enzymes, transcription factors, and
ion channels. In many cases, these actions curtail the use of
ATP and accelerate metabolism to generate more ATP.6
AMPK thus has the potential to influence a broad array of
cellular pathways that regulate energy utilization and production. AMPK might be thought of as the conductor of an
orchestra composed of diverse players that mediate stress
responses in the cell, as will subsequently be enumerated.
Molecular Structure and Function of AMPK
AMPK is actually a complex of 3 different proteins, which
are referred to as the ␣, ␤, and ␥ subunits (Figure 2). Each
subunit has a distinct structure and function; their coordinated
interaction is necessary for changes in the cellular environment to modulate the activity of the AMPK complex. The ␣
subunit contains the catalytic domain of the enzyme, which
transfers a phosphate group from ATP to serine (and occasionally threonine) sites in target proteins. The ␤ subunit
provides a structural bridge between the other subunits and
also contains a specialized sequence that binds to glycogen.
High concentrations of glycogen are present when fuel supply
is abundant, and therefore it is not surprising that glycogen
might inhibit AMPK activation.14,15 Conversely, glycogen
depletion might also contribute to activation of AMPK in the
heart during ischemia16 or exercise.17 The ␥ subunits have an
important regulatory function because they contain the critical binding sites, which enable AMP to activate and ATP to
inhibit the AMPK complex.18
The ␣, ␤, and ␥ subunits each have multiple isoforms, with
minor differences in their amino acid sequences, varying
according to cell type.19 In cardiomyocytes, the ␣2 isoform is
more abundant than the ␣1, which is the sole isoform in
endothelial cells.20 The heart contains the ␥1 and ␥2 isoforms
but lacks the ␥3 isoform that is expressed in skeletal muscle.20
Small structural differences among these isoforms appear to
affect AMPK sensitivity to activation, its location within the
AMPK and Ischemia
833
Figure 2. AMPK complex activation. The AMPK complex is
composed of 3 distinct proteins: The ␣ subunit has enzymatic
activity and transfers a phosphate group from ATP to target
proteins, the ␤ subunit connects the ␣ and ␥ subunits, and the
␥ subunit binds AMP. AMP binding to the ␥ subunit directly
enhances the activity of the AMPK complex. AMP binding also
promotes the phosphorylation of the threonine molecule in the
172cd position of the ␣ subunit (Thr172). Phosphorylation (P) of
AMPK at this amino acid residue greatly increases the activity of
the AMPK complex.
cell, and the proteins that it regulates. For instance, the ␣2
isoform is more sensitive than the ␣1 isoform to changes in
the intracellular AMP concentration.21 This may explain the
observations that both the ␣1- and ␣2-containing complexes
are activated during ischemia,16,20 but the less intense stress
of exercise primarily activates ␣2.17,22 AMPK complexes are
found predominantly in the cytoplasm, where they modulate
energy generating and consuming pathways. However, complexes containing the ␣2 isoform are also present in the
nucleus, where they likely modulate gene expression.21
Mechanisms of Activation of AMPK
In the heart, AMPK is activated by increases in the intracellular concentration of AMP9,23,24 (Figure 2). AMP induces a
conformational change, which directly enhances the activity
of AMPK.25 AMP binding also exposes an important regulatory site (Thr172) in the catalytic ␣ subunit and promotes its
phosphorylation, which substantially increases AMPK activity.26,27 AMP binding renders AMPK less susceptible to the
action of protein phosphatases that remove the phosphate
from the Thr172 site and deactivate AMPK.28,29 ATP normally
blunts these effects of AMP, so that the fall in ATP that
occurs during ischemia augments AMP activation of the
AMPK complex.9,23,24
Upstream enzymes that phosphorylate AMPK and modulate its activity are referred to as AMPK kinases. The tumor
suppressor protein LKB1 was the first such kinase discovered.30,31 Mutations in the human LKB1 gene cause the
Peutz-Jeghers syndrome, an inherited disorder characterized
by gastrointestinal polyps and malignancy.32 The link between LKB1 and AMPK was the first hint that the AMPK
pathway might protect against the development of cancer.
Recent studies also have identified LKB1 mutations in lung
adenocarcinomas.33 LKB1 has a number of additional interesting biological actions, such as directing the intracellular
movement of proteins in a manner that determines cell
polarity in epithelial cells.34 It also prevents programmed cell
death or apoptosis,35 a process that plays a role in organ
development, heart failure, and ischemic injury. LKB1 has an
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Figure 3. Effects of activated AMPK during ischemia and reperfusion. Activated AMPK in the ischemic heart has diverse effects
on metabolic pathways, ion channels, protein synthesis, and
cellular function that modulate the response to ischemia and
reperfusion. The solid lines represent pathways that are stimulated by AMPK, and the dotted lines indicate those that are
inhibited. ER indicates endoplasmic reticulum.
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important role in regulating AMPK in the heart, where the
absence of LKB1 prevents the activation of AMPK complexes containing the major ␣2 isoform during ischemia.36
Although AMPK is an internal energy sensor, it is becoming clear that additional factors influence AMPK activation,
such as the hormones adiponectin37 and insulin.38,39 Adiponectin is an adipocyte-derived hormone, which activates
AMPK and has a protective effect against ischemic injury in
the heart.37 Conversely, insulin inhibits AMPK activation,38,39
which makes teleological sense because insulin levels increase in response to nutrient excess. Insulin and AMPK have
a number of counteracting metabolic effects; insulin promotes glycogen, triglyceride, and protein synthesis, while
AMPK inhibits these energy-consuming processes.6,40
Cardiac AMPK and Exercise
Because AMPK is a fuel sensor that regulates energy generating metabolic pathways, one might anticipate that it would
have a physiological role to modulate the response to exercise. Indeed, exercise stimulates cardiac AMPK activity,17,22
and activated AMPK accelerates the metabolism of fatty
acids and glucose in the heart.23,41,42 However, the extent to
which activated AMPK is essential to energy generation
during exercise remains uncertain. Animals with genetic
alterations that partially inhibit cardiac AMPK appear to
exercise well.22 These findings suggest that additional molecular mechanisms might also trigger metabolic adaptation
during exercise.
Actions of Activated AMPK in the
Ischemic Heart
Activated AMPK has a number of diverse actions during
ischemia. AMPK is known to modulate energy generating
metabolic pathways, cellular protein synthesis, gene expression, ion channel activity, and the function of specialized
organelles in the ischemic heart (Figure 3). In some cases, the
specific molecules that are directly phosphorylated by AMPK
have been identified. In other cases, AMPK has indirect
actions that are mediated through its interaction with additional signaling pathways, such as the nitric oxide pathway.43,44 These latter observations are consistent with the
evolving concept that intracellular signaling pathways function as interwoven networks, which modulate each other.
One of the fundamental responses to ischemia is to
increase cellular glucose metabolism. In the heart, the first
Figure 4. Metabolic actions of activated AMPK. Activated
AMPK modulates both glucose and fatty acid metabolism in the
heart. Activated AMPK stimulates the movement of membrane
transporters to the cardiomyocyte cell surface, where they are
physiologically active, facilitating the entry of glucose and fatty
acids into the cell for subsequent metabolism. Activated AMPK
also directs the enzyme LPL to the capillary endothelium, where
it mediates the uptake of fatty acids from triglyceride-containing
lipoproteins. Within the cardiomyocyte, activated AMPK stimulates cellular energy generation by glycolysis during ischemia
and fatty acid oxidation during reperfusion.
step in glucose utilization is the transport of glucose across
cell surface membranes into the cytosol, where it is actively
metabolized. Cardiac glucose transport is mediated by specific glucose transporter proteins.45 GLUT4 is the primary
cardiomyocyte transporter responsible for glucose uptake in
the ischemic heart.46 When subjected to stress, the heart
recruits GLUT4 transporters from intracellular storage membranes to the cell surface, where they are physiologically
active.45 We now know that activated AMPK provides the
molecular signal that triggers GLUT4 recruitment in the
ischemic heart16,47 (Figure 4). The GLUT4 transporter is not
phosphorylated by AMPK, and the mechanism by which
activated AMPK modulates GLUT4 recruitment in the ischemic heart is not fully understood. Activated AMPK appears to
stimulate GLUT4 recruitment in part through its interactions
with other signaling pathways.44,48 However, the amount of
GLUT4 on the cell surface is also determined by the rate of
recycling of transporters back into intracellular storage membranes. Transporter recycling is also inhibited by activated
AMPK.49 Thus, AMPK regulates the fundamental movement
of glucose transport molecules within the cell and therefore is
critical to the activation of glucose metabolism in the ischemic heart.
AMPK has a central role in the regulation of major
energy-generating metabolic pathways during ischemia as
well as during postischemic reperfusion. The actions of
activated AMPK in the ischemic heart are probably best
understood by first summarizing a few facts about heart
metabolism. Under fasting conditions, the normal heart generates ATP primarily from the oxidation of fatty acids, which
are delivered to the heart as fatty acids bound to albumin or
contained within triglyceride-rich lipoprotein particles. Glucose is an important fuel for the heart after carbohydrate-
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containing meals, which increase insulin levels and decrease
fatty acid concentrations in the plasma. Fuel metabolism in
the heart changes dramatically during myocardial ischemia
because oxidative metabolism is reduced in proportion to the
lack of oxygen delivery. However, ischemia increases the
metabolism of glucose through the glycolytic pathway,42
which generates ATP despite the lack of oxygen. Activated
AMPK in the ischemic heart stimulates the enzyme PFK-2 to
synthesize fructose 2,6-bisphosphate, an activator of PFK1.42 As previously mentioned, PFK-1 is a critical regulator of
glycolysis. Thus, activated AMPK stimulates both glucose
transport into the cell and glycolysis, promoting ATP generation during ischemia.
AMPK also has important influences on metabolism in the
reperfused heart after ischemia. After coronary reperfusion,
metabolism in the postischemic myocardium is an important
determinant of the recovery of contractility and the degree of
ischemic injury. In experiments studying isolated hearts,
AMPK activity typically remains elevated during postischemic reperfusion.16,23 As in the ischemic heart, activated
AMPK is also responsible for the enhanced glucose uptake
that occurs during early reperfusion.16,47 As already mentioned, activated AMPK also inhibits acetyl-CoA carboxylase, the enzyme responsible for the synthesis of malonylCoA.11 Malonyl-CoA is a potent inhibitor of the mitochondrial
enzyme carnitine palmitoyltransferase-1, which facilitates fatty
acid entry into mitochondria for oxidation. By reducing the
synthesis of malonyl-CoA, AMPK thus enhances mitochondria fatty acid oxidation during postischemic reperfusion.11
Activated AMPK also promotes heart fatty acid oxidation
by stimulating the entry of fatty acids into the cardiomyocyte
via the cell membrane transport protein CD36.50 Analogous
to its effect on glucose transporters, activated AMPK stimulates the recruitment of CD36 from intracellular storage
membranes to its active site on the cell surface.50 Additionally, activated AMPK facilitates the uptake of fatty acids
from triglyceride-containing lipoprotein particles,51 which are
an important fuel source for the heart.52 The enzyme responsible for extracting fatty acid molecules from triglycerides is
lipoprotein lipase (LPL). LPL is synthesized by cardiomyocytes but moves to the capillary endothelium, where it
interacts with lipoproteins in the blood.52 Activated AMPK
stimulates the movement of LPL from cardiomyocytes to
endothelial cells.51 Thus, activated AMPK has several physiological effects that act in concert to promote fatty acid
oxidation in the reperfused heart (Figure 4).
Fatty acid oxidation plays an important role in generating energy in the postischemic heart. However, excessive
fatty acid oxidation during reperfusion also impairs glucose oxidation because of inhibition of the mitochondrial
enzyme pyruvate dehydrogenase.2 An imbalance between
glucose uptake and glucose oxidation results in persistent
lactate production that can perpetuate intracellular acidosis
and potentially promote calcium overload after ischemia.2
Particularly under conditions of fatty acid excess, this action
of AMPK can have detrimental effects in the reperfused
heart.2
AMPK and Ischemia
835
Figure 5. AMPK inhibition of protein synthesis. Activated AMPK
modulates protein synthesis by regulating the network of signaling molecules that control the ribosomal machinery responsible
for protein synthesis. Arrows with circled plus signs point to factors whose activity is stimulated. Crossed out arrows represent
pathways that are inhibited when AMPK is activated. Activated
AMPK leads to the downstream inhibition of ribosomal S6
kinase and eEF-2, essential proteins that activate ribosomal protein synthesis.
AMPK and Energy Stores in the
Ischemic Heart
The 2 major high-energy storage molecules in the heart are
ATP and creatine phosphate. As already mentioned, ATP is
the energy source for contractile proteins, ion pumps, and
many enzymes. Creatine phosphate transfers its high-energy
phosphate molecule to ADP and regenerates ATP when
metabolism is impaired and therefore serves as a backup
energy supply in the ischemic heart. In the absence of normal
AMPK activation, both ATP and creatine phosphate are more
severely depleted after ischemia/reperfusion.16,47 These findings have led to the concept that AMPK is an energy guardian
in the ischemic heart.53
AMPK functions as an energy guardian because it lessens
the imbalance between ATP production and consumption
during ischemia/reperfusion. Although much of the preceding
discussion has focused on its role to enhance energy production, an important effect of activated AMPK in the ischemic
heart is to conserve energy.47 AMPK activation is known to
inhibit the energy-consuming processes required to synthesize large macromolecules, such as glycogen, triglycerides,
and proteins. Indeed, turning off the synthesis of new proteins
may be an important effect of activated AMPK in the
ischemic heart.54,55 Although contraction is the major determinant of ATP consumption in the normal heart, contractile
activity quickly diminishes in the ischemic myocardium,
leaving protein synthesis as an important component of
residual myocardial energy expenditure. The addition of each
amino acid onto a nascent protein requires energy in the form
of ATP. Cellular proteins undergo a perpetual process of
synthesis and degradation, which requires significant energy
expenditure. Thus, the action of activated AMPK to inhibit
protein synthesis conserves ATP that can then be utilized for
more vital cellular functions, which might promote short-term
survival during ischemia.
How does activated AMPK inhibit protein synthesis?
AMPK interacts with an elaborate molecular network, which
governs the machinery responsible for protein synthesis
(Figure 5). Each stage of protein synthesis is highly regulated,
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from initiating the translation of the messenger RNA templates that code for the protein to final processing of the
protein. Activated AMPK slows the addition of amino acids
onto nascent proteins by inactivating a protein called eukaryotic elongation factor-2 (eEF-2). AMPK directly activates
eEF-2 kinase, which in turn inactivates eEF-2.56 Thus, AMPK
activation slows the incorporation of amino acids into new
proteins.
Activated AMPK also inhibits protein synthesis by inactivating the well-known protein complex called mammalian
target of rapamycin (mTOR). The mTOR complex is a sensor
of cellular nutrient status. It is activated when amino acids are
readily available to the cell, as well as by insulin and other
growth factors. Activated mTOR stimulates protein synthesis
and cell growth. Rapamycin in drug-eluting stents inhibits
mTOR and thus blocks vascular smooth muscle cell proliferation. How does activated AMPK regulate the mTOR
complex? AMPK inhibits mTOR indirectly by activating the
tuberous sclerosis complex tumor suppressor protein TSC2.57
Human mutations in TSC2 cause hamartomas, presumably
because of unrestrained protein synthesis and cell proliferation. AMPK activation of TSC2 inhibits mTOR activity.57
Because mTOR normally activates the ribosomal S6 kinase
and eukaryotic initiation factor-4, which enhance protein
synthesis, AMPK inhibits protein synthesis.57 Thus, AMPK
activation turns off several components of the protein synthesis machinery and through this mechanism conserves
energy under the duress of ischemia (Figure 5).
AMPK and Ischemic Injury
AMPK activation has a number of important physiological
effects that appear to prevent myocardial injury during
ischemia. Hearts from mice with genetically inactivated
AMPK show impaired recovery of left ventricular contractile
function after ischemia and reperfusion.16,47,58 These hearts
also demonstrate significantly increased myocardial necrosis
after ischemia and reperfusion, indicating that AMPK protects against cell death.16 Although these findings support the
contention that AMPK is cardioprotective in isolated hearts,
many additional factors are operative in the intact organism
that can influence the action of AMPK. Ongoing research
should clarify whether AMPK has a protective effect in
clinically relevant animal models of regional ischemia. The
results of these studies will shed light on whether AMPK
activators might warrant consideration for use in the treatment of myocardial ischemia in the future.
Myocardial necrosis is the primary mechanism responsible
for cell death from ischemia. However, a small amount of
apoptosis or programmed cell death also is induced by
ischemia/reperfusion.59 When AMPK activation is impaired,
apoptosis is substantially increased in hearts subjected to
ischemia/reperfusion.16 AMPK activation also contributes to
the antiapoptotic effects of the hormone adiponectin.37 Thus,
it appears that activated AMPK is also protective in the heart
by limiting apoptosis during ischemia/reperfusion.
AMPK and Ischemic Preconditioning
Recent evidence suggests that AMPK might also protect
against injury by promoting ischemic preconditioning. Ische-
mic preconditioning is an interesting phenomenon through
which short periods of ischemia render the heart less susceptible to injury during subsequent more prolonged ischemic
insults. Ischemic preconditioning is sometimes used to prevent myocardial injury during off-pump coronary bypass
surgery. Short periods of ischemia are induced before occluding the coronary artery in order to perform the distal anastomosis of the bypass graft without injury to the myocardium.
AMPK is activated by short durations of ischemia24 as well as
by experimental preconditioning.60 AMPK has been shown to
induce preconditioning in isolated cardiomyocytes and to
prevent hypoxic injury.61 The degree to which AMPK activation is either required or sufficient to induce preconditioning in the intact heart is uncertain but warrants further
investigation because of its potential clinical application in
preventing ischemic myocardial injury.
The molecular mechanisms responsible for ischemic preconditioning are complex. However, one mechanism through
which activated AMPK might induce ischemic preconditioning is by activating ATP-sensitive potassium channels.61
AMPK stimulates the movement of these channels from
storage membranes to the cell surface membranes, where they
are physiologically active.61 These channels shorten the
action potential and prevent calcium overload during reperfusion. Activated AMPK also stimulates other molecular
signaling pathways, including endothelial nitric oxide synthetase44 and the p38 mitogen-activated protein kinase,48
which appear to have a role in preconditioning. Thus,
activation of AMPK before ischemia has a number of
downstream actions that may serve to protect the heart
against subsequent myocardial injury.
AMPK Regulation of Cellular Organelles
Damage to intracellular organelles promotes injury to cardiomyocytes in the ischemic heart. Mitochondria are very
susceptible to ischemic injury. Damage to the mitochondria
not only impairs their capacity for energy generation but also
leads to the activation of pathways that contribute to necrotic
and apoptotic cell death in the ischemic heart.62,63 AMPK
might lessen mitochondrial damage during ischemia/reperfusion. Recent research also indicates that ischemia induces
alterations in the endoplasmic reticulum, which contribute to
cell injury.64 The endoplasmic reticulum is a processing
center where newly synthesized cellular proteins are folded
into their normal 3-dimensional configurations. The endoplasmic reticulum is subjected to stress when proteins accumulate because of failure to fold during ischemia.64 These
unfolded proteins can trigger apoptotic cell death. Cells
prevent the accumulation of unfolded proteins by slowing
protein synthesis, synthesizing additional chaperone proteins
that assist in the folding process, and degrading unfolded
proteins.64 AMPK plays a role in this compensatory response
by limiting protein synthesis, which reduces the degree of
injury to cardiac myocytes during hypoxia.64
Activated AMPK also regulates intracellular organelles by
modulating a phenomenon that has received recent attention
called autophagy.65 During autophagy, cells digest their own
organelles and large cellular molecules to supply substrates
for energy generation.65 Autophagy is typically triggered by
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severe nutrient starvation. However, cardiomyocyte autophagy has also been described in the hibernating myocardium
and may play a role in maintaining cellular viability in
ischemic cardiomyopathy.66,67 Activated AMPK is involved
in the induction of autophagy.68 Thus, AMPK activation has
diverse effects on organelles, which might affect both shortterm and long-term cardiomyocyte survival in the setting of
myocardial ischemia.
Pharmacological Activators of AMPK
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The possibility that the AMPK pathway might be a target in
the treatment of diabetes, cancer, and cardiovascular disease
has created a great deal of interest in compounds that activate
AMPK. For many years, the agent that was used for investigative purposes was the compound 5-aminoimidazole-4carboxamide-1-␤-4-ribofuranoside, more commonly referred
to as AICAR. AICAR is phosphorylated in the cell and
mimics the effect of AMP to activate cardiac AMPK.41,44
However, AICAR also prevents the reuptake of adenosine
after release from the ischemic heart and thereby augments
activation of membrane adenosine receptors. AICAR was
patented as Acadesine and underwent clinical trials during
coronary bypass surgery.69 It proved to have benefit to
prevent myocardial infarction, the need for left ventricular
assist device support, and early death.69 However, the fact
that AICAR activates AMPK was not appreciated at that
time, and it remains unclear whether the doses used in
previous clinical trials effectively activated AMPK in the
human heart.
There is now a great deal of effort in the development of
specific AMPK activators. Such agents are currently the
focus of several drug discovery programs, most of which are
targeted at the treatment of type 2 diabetes. The first prototype drugs are now emerging,70 and their effects on the heart
will be of substantial interest.
Cardiomyopathy Associated With Mutations
in the AMPK ␥2 Gene
Given the numerous physiological actions of activated
AMPK, it is not surprising that mutations that disrupt the
normal regulation of the AMPK complex are associated with
abnormalities in the heart. There are 10 distinct human
mutations that have been identified in the PRKAG2 gene,
which encodes the AMPK ␥2 subunit protein.7 As mentioned
previously, the ␥ subunits contain the critical AMP-binding
sites that modulate AMPK complex activity. Patients with
PRKAG2 mutations demonstrate left ventricular hypertrophy,
Wolff-Parkinson-White syndrome, arrhythmias, conduction
system disease, and heart failure.7,71,72 Affected individuals
demonstrate cardiomyocyte glycogen overload,73 which is
thought to have a primary role in the pathogenesis of disease.
Interestingly, the clinical manifestations associated with the
PRKAG2 mutation are reminiscent of classic glycogen storage disorders, such as Danon and Pompe diseases.7
The clinical manifestations depend somewhat on the specific mutation but also vary within families with the same
mutation.7 Most patients demonstrate left ventricular hypertrophy and/or Wolff-Parkinson-White syndrome.7,74,75 Pathologically, these individuals have increased left ventricular
AMPK and Ischemia
837
wall thickness with substantial glycogen overload but not the
typical myofibrillar disarray and hypertrophy associated with
classic hypertrophic cardiomyopathy.7 Left ventricular hypertrophy can develop during childhood and is sometimes
associated with ventricular outflow track obstruction, cavity
dilation, and heart failure.75 Wolff-Parkinson-White syndrome is also commonly associated with PRKAG2 mutations.7,74 Ventricular preexcitation results from bands of
glycogen-loaded cardiomyocytes that function as electric
bypass tracks connecting the atria and ventricles.7 Excess
glycogen is thought to inhibit the process of apoptosis that
normally eliminates these cardiomyocytes during the development of the annulus fibrosis.7 Persistence of these cardiomyocyte bands can produce single or sometimes multiple
functional bypass tracks in patients with PRKAG2
mutations.7
The reason for glycogen overload in these hearts has been
elucidated through the recent study of transgenic mice expressing PRKAG2 mutations.76 –79 Perhaps the best understood is the N488I mutation, which results in the substitution
of an isoleucine for the normal asparagine at the 488th
position in the AMPK ␥2 protein. This mutation leads to
abnormally high baseline AMPK activity,77 which is directly
linked to the development of glycogen overload, cardiac
hypertrophy, and ventricular preexcitation.80 Excess glycogen
results from accelerated glycogen synthesis81 rather than the
impaired breakdown that is characteristic of classic glycogen
storage diseases. As already discussed, activated AMPK
increases cellular glucose uptake.41 It also increases fatty acid
oxidation,23 which blocks glucose oxidation and thus increases the amount of intracellular glucose that is available to
synthesize glycogen.81 Thus, cardiac glycogen overload associated with the PRKAG2 mutations appears to be due to a
remodeling of glucose metabolism that enhances glucose
uptake and preferentially shunts glucose into glycogen.81
Future Clinical Directions
The actions of activated AMPK previously described have
generated many questions regarding its potential role in
cardiovascular disease. There is considerable interest in
whether AMPK activation might indeed protect the heart
against myocardial injury. To the extent that activated AMPK
effectively preconditions the heart, novel pharmacological
approaches to AMPK activation could prove useful before
high-risk revascularization procedures. Additional applications might include protecting donor hearts before transplantation and treating patients with acute ischemic syndromes
who do not have access to immediate revascularization.
The role of AMPK in cardiovascular disease is not limited
to the ischemic myocardium. AMPK may prove to have an
important role in the vasculature. Activated AMPK affects
endothelial metabolism and function,82,83 vascular smooth
muscle proliferation,84,85 and angiogenesis.86,87 Like rapamycin, activated AMPK inhibits the mTOR pathway and could
potentially have a role in preventing restenosis after coronary
intervention. It is intriguing to consider whether the AMPK
pathway could be modulated as a means of preventing
atherosclerosis, restenosis, or transplant vasculopathy.4
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AMPK also has important metabolic effects outside of the
heart that might be useful in the treatment of type 2
diabetes.3,5 Activated AMPK stimulates skeletal muscle glucose uptake88 and suppresses the release of glucose from the
liver.89 Activated AMPK also improves insulin receptor
signaling.90 It is of interest to note that both metformin91,92
and thiazolidinediones93,94 stimulate AMPK activity. Because
diabetic and insulin-resistant patients are highly prone to
cardiovascular disease, the potential that AMPK-directed
therapy might have simultaneous metabolic, cardiac, and
vascular effects would be of obvious clinical interest.
When clinical applications are considered, targeting a
major conductor of the stress signaling orchestra, rather than
a single player, has enormous potential to direct a widereaching biological response. However, despite substantial
enthusiasm for examining AMPK as a therapeutic target,
there are concerns that such a strategy is inherently more
complex than one focused on a single player. For instance, it
is possible that some orchestral players might indeed be out
of tune with the desired therapeutic response. Thus, preclinical research is essential to evaluate the effects of AMPK
activators in clinically relevant models of disease.
It seems likely that the application of AMPK activators to
the heart would be limited to short-term use. However, if
strategies are developed for the long-term use of AMPK
activators for other diseases, particular attention will need to
be given to evaluate whether they cause glycogen accumulation in the adult heart. AMPK activation also has an antisatiety action in the hypothalamus,95 which might cause unwanted weight gain; to the extent that this occurs, drugs
would need to be designed with chemical structures that
would avoid entry into the central nervous system.
Over the last decade, there have been major advances in
understanding the AMPK pathway, which provide a rationale
for further research to explore the potential for AMPKdirected therapy for important problems in clinical medicine.
As drugs are developed that effectively modulate this pathway, clinicians practicing cardiovascular medicine are likely
to hear more about this conductor of the cardiac stress
response orchestra.
4.
5.
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7.
8.
9.
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12.
13.
14.
15.
16.
17.
18.
19.
Acknowledgments
20.
The author acknowledges the important contribution of discussions
with Drs Ji Li, Raymond R. Russell III, Edward J. Miller, Agnes
Kim, and Dake Qi to this article.
21.
Sources of Funding
This work was supported in part by a grant from the US Public
Health Service (RO1 HL63811).
Disclosures
None.
22.
23.
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KEY WORDS: AMP kinase
transduction
䡲
fatty acids
䡲
glucose
䡲
ischemia
䡲
signal
AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra
Lawrence H. Young
Circulation. 2008;117:832-840
doi: 10.1161/CIRCULATIONAHA.107.713115
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