J. Biomedical Science and Engineering, 2013, 6, 1085-1089 JBiSE
http://dx.doi.org/10.4236/jbise.2013.611136 Published Online November 2013 (http://www.scirp.org/journal/jbise/)
An AMPK paradox in pulmonary arterial hypertension
Miranda Sun, Guofei Zhou*
Department of Pediatrics, University of Illinois at Chicago, Chicago, USA
Received 27 September 2013; revised 29 October 2013; accepted 8 November 2013
Copyright © 2013 Miranda Sun, Guofei Zhou. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Adenosine monophosphate-activated protein kinase
(AMPK) is a heterotrimeric serine-threonine kinase
important as a metabolic sensor for intracellular ATP
levels and plays a key role in regulating cell survival
and proliferation, particularly when cells are exposed
to hypoxia. AMPK is critical for lung function, and
abnormal AMPK signaling participates in many lung
diseases. Recent studies suggest that both inhibition
and activation of AMPK are preventive for the de-
velopment of pulmonary arterial hypertension (PAH).
However, the molecular mechanisms by which inhibi-
tion or activation of AMPK affects pulmonary hy-
pertension (PH) appear to be distinct. Inhibition of
AMPK by compound C blocks hypoxia-induced auto-
phagy and induces apoptosis in pulmonary artery
smooth muscle cells, leading to prevention of PAH;
activation of AMPK by metformin attenuates the PH
phenotype induced by hypoxia by regulating endothe-
lial cell function. These seemingly opposing data on
the function of AMPK in PH can be partly explained
by off-target and compartment-specific effects of
AMPK inhibitors and activators and the differenti-
ated expression of AMPK in various cell types and
subcellular locations. To elucidate the specific roles of
AMPK in the pathogenesis of PAH, it is important to
study the role of AMPK in a tissue specific manner
combining genetic and biochemical approaches.
Keywords: AMPK; Pulmonary Hypertension;
Pulmonary Artery Smooth Muscle Cells; Endothelial
Cells
1. INTRODUCTION
Pulmonary arterial hypertension (PAH) is a disease cha-
racterized by increased pulmonary arterial pressure that
leads to right ventricular failure, and ultimately, death
[1,2]. Active vasoconstriction as well as vascular remod-
eling leads to manifestation of the disease. Pulmonary
artery remodeling includes survival and proliferation of
pulmonary artery smooth muscle cells (PASMC), which
cause the development and progression of high pulmo-
nary vascular tone observed in PAH patients [3]. Hy-
poxia-induced pulmonary hypertension (PH) in several
animal models is a well-established and commonly em-
ployed method to investigate the pathogenesis of PAH.
Hypoxia is known to induce right ventricular hypertro-
phy (expressed as a ratio of right ventricular weight to
left ventricular plus ventricular septum weight, RV/(LV +
S), increased pulmonary arterial pressure, and pulmo-
nary arterial wall remodeling [4]. Although major ad-
vancements have been made in the last two decades in
the understanding of the development and treatment of
PAH, the exact mechanisms in the pathogenesis are still
not clear and there is currently no cure for this disease.
Adenosine monophosphate-activated protein kinase
(AMPK) is a heterotrimeric serine-threonine kinase im-
portant as a metabolic sensor for intracellular ATP levels
[5]. AMPK is composed of three subunits, the catalytic α
subunit and the regulatory β and γ subunits. Each of the
subunits can be found in multiple isoforms (α 1, α 2, β 1,
β 2, γ 1, γ 2, γ 3), giving a total of 12 combinations hav-
ing different tissue distribution and subcellular localiza-
tion patterns [5,6]. AMPK is allosterically activated by
the binding of two AMP molecules to the γ subunit, al-
lowing the phosphorylation of α Thr 172 in the catalytic
domain via an upstream kinase, thus increasing kinase
activity, and inhibiting AMPK dephosphorylation [5].
AMPK is sensitive to stress and low energy states when
the AMP/ATP ratio increases, such as in hypoxia. AMPK
is also considered a “master switch” in regulating cell
survival and proliferation. For example, AMPK activity
is increased in rapidly proliferating cells like cardiac
fibroblasts and cancer cells [7,8]. In addition, cell cycle
regulation, decision to enter autophagy, apoptosis, and
other cell fate decisions are regulated by AMPK (Figure
1) [9].
*Corresponding author.

M. Sun, G. F. Zhou / J. Biomedical Science and Engineering 6 (2013) 1085-1089 1086
Autophagy
AMPK
Cell proliferation
Apoptosis Cell survival
Figure 1. Schematic diagram of the roles of AMPK in the cel-
lular response to hypoxia.
In the lung, both isoforms of the catalytic α subunit are
expressed [5,10,11]. Accumulating evidence suggests
that AMPK is critical for lung function, and abnormal
AMPK signaling participates in lung disease [10,12-16].
For example, in alveolar epithelial cells, AMPK is criti-
cal for the regulation of sodium transport [12,13,16]. Re-
cent reports also suggest that acute or moderate hypoxia
can activate AMPK through Ca2+/calmodulin-dependent
protein kinase kinase-β (CaMKKβ) independent of the
AMP/ATP ratio [13-15]. In pulmonary endothelial cells,
AMPK promotes endothelial barrier function [10]. PA-
SMC express both α isoforms, of which the α 1 isoform
contributes up to 80% of the total AMPK activity [5].
However, the role of AMPK in lung, particularly in PAH,
appears to be inconclusive: We have shown that AMPK
inhibition is beneficial for the treatment of PH [17] where-
as others suggest that AMPK activators such as met-
formin and AICAR are protective against experimental
PH [18]
(http://licensing.inserm.fr/fiche.php?artid=179). In this
review, we will present an overview on the current lit-
erature on the role of AMPK in PAH, analyze the causes
of discrepancy, and discuss the future directions to elu-
cidate the role of AMPK in the lung.
2. INHIBITION OF AMPK PREVENTS
AND REVERSES HYPOXIA-INDUCED
PH
Recently, we have demonstrated the physiological sig-
nificance of AMPK in PAH [17]. In human pulmonary
artery smooth muscle cells (HPASMC) isolated from
PAH patients, levels of AMPK phosphorylated at α Thr
172 (pAMPK) are elevated compared to normal HPA-
SMC while total AMPK levels remained the same. In a
hypoxia-induced PH mouse model, pAMPK in the lung
tissue of mice exposed to hypoxia for three weeks is also
increased, and elevation of pAMPK occurs in mouse
PASMC. These results suggest that AMPK is hyper-
phosphorylated in PASMC of PAH.
We also report that AMPK is necessary for PASMC
survival in hypoxia [17]. HPASMC treated with com-
pound C, an AMPK inhibitor, exhibit decreased viability
in hypoxia compared to untreated HPASMC, while inhi-
bition of AMPK in normoxia using compound C has no
effect on viability. As PASMC express both α 1 and α 2
isoforms of AMPK, the two different isoforms of the
catalytic subunit are found to regulate separate functions
that prevent cell death in hypoxia. Specifically, AMPK α
2 promotes HPASMC survival by increasing expression
of pro-survival proteins such as MCL-1. On the other
hand, AMPK α 1 functions through regulating autophagy.
The inhibition of AMPK α 1 prevents autophagy and,
thus, causes cell death independent of apoptosis (Figure
2).
Furthermore, using an in vivo mouse model, we show
that inhibition of AMPK by compound C is able to pre-
vent the development of hypoxia-induced PH when
compound C is administered before a three-week hy-
poxia exposure. When mice are treated with compound C
prior to hypoxia exposure, they have significantly re-
duced RV/(LV + S) ratio, right ventricular systolic pres-
sure (RVSP), and vascular remodeling (arterial wall
thickness). Compound C can also partially reverse hy-
poxia-induced PH when it is administered after the onset
of hypertension. In this model, mice are exposed to hy-
poxia for two weeks to induce hypertension and are then
treated with compound C. RV/(LV + S) ratio and vessel
wall thickness are significantly reduced, but RVSP was
not affected. In both models, a marker of hypoxia, HCT,
is unaffected by compound C treatment, suggesting that
it is unlikely that compound C affects hypoxia-induced
PH though an off-target effect on HIF. These results in-
dicate that an inhibitor of AMPK may be a novel thera-
peutic approach for the treatment of PAH.
3. ACTIVATION OF AMPK PLAYS A
PROTECTIVE ROLE AGAINST PH
Metformin, a commonly used drug for treating type 2
diabetes mellitus, has recently been shown to treat PH in
animal models. Metformin improves hyperglycemia by
increasing peripheral sensitivity to insulin, reducing gas-
AMPK α 1 Autophagy Cell Death
Apoptosis MCL-1
Hypoxia
AMPK α 2
Figure 2. The mechanism by which activation of APMK pro-
motes PASMC survival during hypoxia. Activation of AMPK α
1 and α 2 during hypoxia plays a differentiated role in the sur-
vival of PASMC: Activation of AMPK α1 induces hypoxia-
induced autophagy, preventing PASMC death; activation of
AMPK α2 maintains the expression levels of MCL-1 during
hypoxia, preventing cell apoptosis.

M. Sun, G. F. Zhou / J. Biomedical Science and Engineering 6 (2013) 1085-1089 1087
trointestinal absorption of glucose, and inhibiting glucose
production by the liver [19,20]. In addition, metformin
has been shown to improve cardiovascular function [21].
Studies have demonstrated that metformin carries out a
large part of these functions through activation of AMPK
[18,22].
Agard et al. have demonstrated that metformin exhib-
its a protective effect against hypoxia-induced PH in a rat
model [18]. Rats exposed to hypoxia while being treated
with metformin showed near normal levels of pulmonary
arterial pressure, RV wall thickness, and RV/(LV + S)
ratio, with the effect being dependent on drug dose. In
addition, metformin treatment significantly reduced pul-
monary artery remodeling in the lungs of hypoxic rats.
As expected, there was an increase in the phosphoryla-
tion of acetyl CoA carboxylase, a direct target of AMPK,
in the pulmonary arteries of metformin-treated hypoxic
rats, demonstrating an increase in AMPK activity. This
study also demonstrates attenuation of hypoxic pulmo-
nary vasoconstriction due to improved endothelial func-
tion and decreased RhoA/Rho kinase activity after treat-
ment with metformin, which is in agreement with previ-
ous studies on metformin and vascular tone [22-24].
Furthermore, treatment with metformin on cultured rat
PASMC inhibited proliferation. Consistently, AICAR,
another AMPK activator, has also been shown to be pro-
tective against experimental PH [18]
(htt p://licensing.inserm.fr/fiche.php?artid=179). Thus, these
studies suggest that an AMPK activator may be used as
therapeutic agent for the treatment of PAH.
4. DISCUSSION
In this review, we have discussed seemingly opposing
data on the function of AMPK in PAH and hypoxia mod-
els of PH. On the one hand, we have suggested that inhi-
bition of AMPK activity prevents and reverses hypoxia-
induced PH by inducing PASMC death; on the other
hand, Agard et al. have suggested that activation of
AMPK protects against hypoxia-induced PH, presuma-
bly by regulating endothelial cell function [18]. However,
these results need to be viewed with caution due to non-
specific effects of these drugs. This inconsistency can
therefore be explained partly by off-target and compart-
ment-specific effects of AMPK inhibitors and activators
[25-27] and partly by the differentiated expression of
AMPK in various cell types and subcellular locations
[5,10,28].
Indeed, the role of AMPK in cell survival, for example,
appears to be cell-specific. Some studies show that
AMPK is activated in rapidly proliferating cells [7,8] and
that inhibition of AMPK induces growth arrest and re-
duces viability [8,29]. Others report that activation of
AMPK inhibits growth and/or survival of cells, particu-
larly in systemic vascular smooth muscle cells [30-32].
Our study demonstrates that AMPK α 1 plays a role in
regulating autophagy while AMPK α 2 upregulates the
pro-survival protein MCL-1, inhibiting apoptosis. Both
isoforms are necessary for PASMC survival in hypoxia;
however, suppression of either or both isoforms does not
induce cell death under normoxic conditions. Krymskaya
and colleagues show that hypoxic activation of AMPK
does not contribute to hypoxia-induced proliferation of
PASMC [33], supporting our finding that the role of
AMPK in hypoxia-induced PH is mediated by its regula-
tion of PASMC survival. In addition, AMPK is known to
be required for hypoxia-mediated vasoconstriction [5,34,
35], a feature of PAH. Thus, these studies suggest that
activation of AMPK contributes to the pathogenesis of
PAH.
In the study by Agard et al., however, indirect AMPK
activation by the drug metformin seems to attenuate, and
almost eliminate, PAH phenotype induced by hypoxia.
An increase in the phosphorylation of endothelial NOS
(eNOS) as a marker of endothelial function and a de-
crease in phosphorylated MYPT as a marker of RhoA/
Rho kinase activity were observed. Improvement in en-
dothelial function is likely mediated by AMPK activity
as several previous studies have shown AMPK activity
to lead directly to phosphorylation of eNOS [22,24]. It is
worth pointing out that the inhibition of PASMC prolif-
eration with metformin treatment is possibly due only in
part to AMPK activity. Previous studies on metformin’s
inhibitory effects on cancer cell proliferation were shown
to be only partly dependent upon AMPK [36,37]. There-
fore, the protective effects of metformin from hypoxia-
induced PH may not be completely attributed to in-
creased AMPK activity.
In conclusion, recent studies have shown what seems
like opposite functions for AMPK in PAH. However, in
reconciliation, the molecular pathways and the type of
cells in which AMPK functions are different. In one set
of studies, inhibition of AMPK leads to elevated PASMC
cell death, thus preventing PH; in another set of studies,
AMPK activation increases eNOS function to attenuate
PH. Given the fact that these studies are carried out with
chemical AMPK inhibitors and activators, these results
need to be interpreted with caution as long-term success
in the treatment of PAH with these agents being uncer-
tain due to their non-specific effects [27]. Thus, to eluci-
date the specific roles of AMPK in pathogenesis of PAH,
it is important to study the role of AMPK in a tis-
sue-specific manner combining genetic and biochemical
approaches.
5. ACKNOWLEDGEMENTS
This study was supported in part by a Pulmonary Hypertension Asso-

M. Sun, G. F. Zhou / J. Biomedical Science and Engineering 6 (2013) 1085-1089 1088
ciation/Pfizer Proof-of-Concept award (G. Zhou) in which American
Thoracic Society provides administrative support.
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