Cardiovascular Research (2012) 95, 403408 REVIEW

doi:10.1093/cvr/cvs166

PI3Kg in hypertension: a novel therapeutic target

controlling vascular myogenic tone and target
organ damage
Daniela Carnevale 1,2 and Giuseppe Lembo 1,2*

Downloaded from http://cardiovascres.oxfordjournals.org/ at Universiti Kebangsaan Malaysia on March 15, 2013

1
Department of Angiocardioneurology, IRCCS Neuromed, Pozzilli (IS), Italy; and 2Department of Molecular Medicine, Sapienza University of Rome c/o IRCCS Neuromed, Pozzilli (IS), Italy

Received 6 February 2012; revised 25 April 2012; accepted 16 May 2012; online publish-ahead-of-print 19 May 2012

Abstract In the past decade, several studies have characterized a number of cellular and molecular mechanisms that contribute
to the regulation of the vascular myogenic response, thus affecting blood pressure regulation. Recently, phosphoino-
sitide 3-kinase g (PI3Kg) has been identified as a main regulator of vascular myogenic tone and blood pressure, a
result further strengthened by a highly significant genome-wide association of a single nucleotide polymorphism flank-
ing this gene with blood pressure regulation, in a large human population. The goal of this review is to summarize the
available information regarding the mechanism whereby PI3Kg exerts blood pressure control, regulating myogenic
tone at the level of L-type calcium channel in smooth muscle cells. Moreover, an overview of the pharmacological
approaches available for targeting this signalling pathway shows that PI3Kg is a suitable candidate for antihypertensive
therapy, capable of lowering blood pressure. Finally, a survey of the studies dissecting the role of PI3Kg in pathological
conditions that are typically induced by hypertension in its target organs provides a more complete picture of the
high potential of this novel therapeutic approach for fighting hypertension and, at the same time, its target organ
damage, independently of blood pressure-lowering effects.
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Keywords Phosphoinositide 3-kinase g Myogenic tone Cell signalling Inflammation Signal transduction

with three phases.9 The first phase, consisting of the development

1. Introduction
Arterial hypertension is a cardiovascular risk factor and a major
healthcare problem.1 So far, although it is well known that the vascu-
lature, kidney, and central nervous system contribute to the develop-
ment of hypertension,1 the molecular pathophysiological mechanisms
involved in the onset of higher blood pressure have not been com-
pletely clarified. However, it is generally recognized that both
human hypertension and experimental models of hypertension are
mainly characterized by increased peripheral vascular resistance.2 4
Indeed, whatever the primary challenge leading to high blood pressure
levels, the establishment of a chronically hypertensive state involves
functional and structural adaptation in resistance arteries.5 In particu-
lar, elevation of intravascular pressure causes constriction of vascular
smooth muscle cells (VSMCs) in resistance arteries, and this behav-
iour, known as myogenic tone, is a key element for maintenance of
blood pressure.6 8 Moreover, this myogenic behaviour, which has
also been demonstrated to occur independently of neural control in
isolated vessels, is considered to be an intrinsic function of the
smooth muscle vessel wall,5 and can be described in general terms
of myogenic tone or basal tone, is associated with a large increase
in intracellular calcium via flux through the L-type voltage-gated
calcium channel (LTCC). In the second phase, there is a further con-
striction in response to an increase in intraluminal pressure, with no
additional change in intracellular concentrations of calcium, but with
a calcium sensitization of the mechanical apparatus inside the cell. In
the final phase, when the arterial wall is unable to maintain a constric-
tion against mounting pressures, a forced dilatation could happen.10
In the past decade, several studies have begun to yield insights into
the cellular and molecular mechanisms contributing to the regulation
of the vascular myogenic response and novel intracellular pathways
that regulate it positively or negatively, affecting blood pressure,
have been characterized. In particular, innumerable signalling pathways
involved in the initiation, maintenance, and control of myogenic tone
and autoregulation have been identified, and include changes in intra-
cellular calcium, protein kinases, and diacylglycerol, as well as modu-
lation of ions and transient receptor potential-like channels.10
Here, we review pathophysiological functions of phosphoinositide
3-kinase (PI3K) signalling in the cardiovascular system. In particular,

* Corresponding author. Tel: +39 0865 929644; fax: +39 0865 927575, Email: giuseppe.lembo@uniroma1.it and lembo@neuromed.it
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.com.
404 D. Carnevale and G. Lembo

we discuss the involvement of the g-isoform in the regulation of vas-

cular tone and blood pressure, revealing a novel signalling pathway Table 1 PI3K family: classification, distribution, and
that is targeted to fight hypertension. composition
On this issue, recent evidence in humans11 emphasizes that phos- Cell types Catalytic Regulatory
phoinositide 3-kinase g (PI3Kg), a lipid and protein kinase that we subunit subunit
have recently identified as being a main regulator of vascular myogenic ....................................................................................
tone,12 is an emerging suitable candidate for therapeutic intervention Class IA
in hypertension. In particular, the International Consortium of Blood PI3Ka Ubiquitous p110a p85a (p55a, p50a);
p85b; p55g
Pressure Genome-Wide Association Studies (ICBP-GWAS) found a
PI3Kb Ubiquitous p110b
genome-wide significant association, in 120 000 individuals, of six
PI3Kd Leucocytes and p110d
new loci influencing pulse pressure (PP) and mean arterial pressure
cardiovascular
(MAP).11 Among these, the single nucleotide polymorphism (SNP) tissues
rs17477177 on chromosome 7q22.3 caught our attention, because Class IB
this SNP flanks the region PIK3CG encoding for PI3Kg (the most sig- PI3Kg Leucocytes and p110g p101, p84/87

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nificant association, with P 2.3 10213). This genome-wide associ-
ation of a new locus flanking the PIK3CG region in PP and MAP
strengthens our findings in experimental models, showing a patho-
physiological link between PI3Kg and blood pressure regulation.12,13
In particular, the authors have studied the associations of risk
scores with hypertension and blood pressure-related outcomes, in-
cluding coronary heart disease, heart failure, stroke, echocardiographic
measures of left ventricular structure, pulse wave velocity, renal func-
tion, and renal failure. The PP SNPs risk score was associated with
prevalent hypertension, incident stroke, and coronary heart disease,
while the MAP SNPs risk score was associated with hypertension,
coronary heart disease, stroke, and left ventricular wall thickness,
thus confirming the clinical relevance of the reported measures of
blood pressure phenotype.11 The discovery of the genome-wide asso-
ciation between the SNP flanking the region encoding PIK3CG and PP/
MAP11 not only brings to light the human counterpart of our findings
in mice,12,13 but also suggests the possibility for translating to humans
the use of PI3Kg inhibitors as novel tools to treat hypertension.
2. PI3K family: an overview
Phosphoinositide 3-kinases are a conserved family of enzymes
involved in intracellular signal transduction, and are characterized by
dual protein and lipid kinase activity.14,15 Members of this family
differ in protein structure, expression, regulation, and substrate speci-
ficity, but all share a common catalytic function; they phosphorylate
the 3-hydroxyl group of the inositol ring of three species of phosphati-
dylinositol (PtdIns) lipid substrates, namely, PtdIns, PtdIns-4-phosphate
(PtdIns4P) and PtdIns-4,5-bisphosphate [PtdIns(4,5)P2].15
Historically, PI3Ks have been divided into three classes (class I, class
II and class III), based on structural and functional aspects (Table 1).
Class IA and IB PI3Ks are heterodimeric enzymes composed of a
regulatory adapter subunit coupled to a tightly bound catalytic
subunit, and they are the only PI3Ks that phosphorylate
PtdIns(4,5)P2 to PtdIns(3,4,5)P3. Class IA catalytic subunits include
p110a, b, and d, whereas the class IB catalytic subunit is p110g.
PI3Ka and b are ubiquitous and abundantly expressed.16 The expres-
sion of PI3Kd and g has been considered for a long time to be
restricted mainly to leucocytes;16 however, the expression of PI3Kg
has recently also been described in several cells of the cardiovascular
system, including cardiomyocytes, vascular endothelial and smooth
muscle cells, and platelets.17,18 A peculiarity of this enzyme is its cap-
ability to exert both kinase-dependent and kinase-independent
actions. For Class II PI3Ks, three different monomers, producing
cardiovascular
tissues
Class II
PIK3-C2a Ubiquitous
PIK3-C2b Ubiquitous
PIK3-C2d Liver specific
Class III
Vps34 Ubiquitous Vps34-like p150
(PIK3-C3 in
mammals)
PtdIns(3)P from PtdIns, have been identified: the ubiquitous
PI3K-C2a and C2b, and the liver-specific PI3K-C2g.14,15 The vacuolar
protein sorting 34 (Vps34), a ubiquitously expressed protein, is the
only member of class III, and generates only PtdIns(3)P.14,15
Upon receptor tyrosine kinase and G-protein-coupled receptor
(GPCR) stimulation or Ras activation, these 3-phospho-inositides co-
ordinate the localization and function of multiple effector proteins,
which bind these lipids through specific lipid-binding domains, namely
the pleckstrin homology domain, the phox homology domain, and the
Fab 1, YOTB, Vac 1, and EEA1 domain. These domains, by binding phos-
phorylated phosphatidyl-inositols, facilitate the recruitment of down-
stream effectors to the plasma membrane. Protein kinase B (PKB/
Akt), a serinethreonine kinase, is the archetypal enzyme activated by
PI3Ks. Akt1, among the three different Akt isoforms, plays the most
relevant role in cardiovascular functions.19 Other effectors able to
bind PI(3,4,5)P3, through the pleckstrin homology domain, include
glycogen synthase kinase 3, Raf, forkhead box transcription factors,
RhoA, phospholipase C and guanine nucleotide exchange factors for
small GTPases, all with a potential involvement in the cardiovascular
system.20 Another level of regulation of PI(3,4,5)P3 is due to the oppos-
ite action of PI3Ks and distinct phosphatases, such as SHIP1 and SHIP2
(SH2-containing inositol phosphatase) as well as PTEN (phosphatase
and tensin homologue), which dephosphorylate the inositol ring of
this lipid at position 5 or 3, respectively.21 24
Among the several PI3K isoforms, class I PI3Ks are the
best-characterized isoforms, whereas less is known about class II
and class III, particularly in the cardiovascular system. Given the
wide distribution of PI3Ks, a global inhibition would probably be dele-
terious to organisms. For this reason, the identification of roles and
mechanisms of action of PI3K isoforms in normal physiology and
disease has become a compelling mission in order to find drugs that
target specific PI3K isoforms.
PI3Kg and hypertension
3. PI3Kg in hypertension
Since its initial description, the g-isoform of PI3K has been considered
to be almost exclusively expressed by leucocytes.16 Nevertheless, an
increasing number of studies in the last decade, prompted by the fact
that PI3Kg is the typical isoform activated by GPCRs, and the fact that
GPCR signalling is historically recognized as crucial for the modulation
of cardiovascular physiology, allowed recognition of a complex
pattern of expression that includes the presence of PI3Kg in tissues
other than immune cells. Another fascinating aspect that stimulated
the search for roles of PI3Kg outside the immune system was the
common relay of environmental stress signals to cells of the cardio-
vascular and immune systems, following a series of intriguingly
similar pathways, among which calcium regulation appears to be a re-
markably recurring theme.25,26 Thus it became increasingly clear that
PI3Kg is widely distributed in many cells of the cardiovascular system,
namely cardiomyocytes, endothelial cells, vascular smooth muscle
cells, and platelets.20
The availability of genetically modified mice lacking PI3Kg opened
up the possibility for study of its function in the cardiovascular
system in vivo, bringing to light a novel molecular target in cardiovas-
cular diseases.27 32
The finding that PI3Kg signalling was also active in smooth muscle
cells prompted the study of the function of this enzyme in the delicate
balance between vasorelaxation and vasoconstriction induced by the
vast variety of vasoactive GPCR agonists.13,33 36
Interestingly, several studies have reported a role for PI3K in
smooth muscle contractility induced by the GPCR agonist
angiotensin II (Ang II),33 37 and PI3Ks have long been considered as
crucial signal transduction elements downstream of Ang II receptors.
However, the nature of the PI3K isoform remained elusive for a long
time, until the use of antibodies that selectively block PI3Kg proved to
be effective in inhibiting Ang II-induced production of PtdIns(3,4,5)P3
and influx of calcium in rat portal vein myocytes.34
These data strongly suggested that Ang II requires PI3Kg to stimu-
late calcium channels in smooth muscle and induce the calcium influx,
thereby governing the vascular contractile response, a process that is
mainly controlled by LTCCs. Indeed, an anti-PI3Kg antibody
(anti-PI3K p110g; Santa Cruz Biotechnology, Santa Cruz, CA, USA)
blocked the Ang II-dependent activation of LTCCs in portal myocytes,
thus demonstrating that this enzyme is the link between Ang II recep-
tors and extracellular Ca2+ influx.34
However, the idea of a crucial role for PI3Kg in the regulation of vas-
cular tone came when researchers in our laboratory found that mice
lacking PI3Kg are protected from the hypertensive effect of chronic
Ang II exposure.13 Moreover, the absence of PI3Kg, as well as the ex-
pression of a PI3Kg kinase-dead mutant, causes a significant reduction
in Ang II-evoked L-type Ca2+ influx and contractility in whole vessels.13
Viard et al., shortly before, showed that in nervous system cells the
PI3K-induced calcium entry occurs through the phosphorylation of
the Cavb2a subunit of the LTCC on an Akt consensus site, which pro-
motes its translocation to the plasma membrane.37 Notably,
researchers in our laboratory found in resistance arteries that the mo-
lecular link between PI3Kg and LTCCs was the kinase PKB/Akt,
because the expression of a dominant negative PKB/Akt mutant in
vessels dramatically reduces Ang II-evoked vasoconstriction.13
More recently, we have revealed, for the first time, that inhibition of
kinase-dependent PI3Kg signalling, as well as of its downstream signal-
ling, Akt, is able markedly to impair the vascular myogenic tone, in an
405
experimental setting for isolated vessels where the myogenic re-
sponse to perfusion pressure represents the main component of vas-
cular tone, in the absence of any neurohormonal influence.12 On this
issue, it is tempting to regard PI3Kg/Akt signalling as one of the main
pathways recruited by pressure-induced mechanical stress and strictly
required for establishment of myogenic tone in response to increases
in intraluminal pressure in resistance arteries.
Furthermore, our novel data on PI3Kg have added a further piece
of knowledge on how this signalling pathway regulates myogenic tone
in resistance arteries, by finely tuning LTCC activity.
As stated above, a main role in myogenic vascular contraction is
played by calcium influx through LTCCs. Signalling through Akt is of
key importance for the structural organization and functionality of
the LTCC complex at the plasma membrane. In particular, regulation
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of LTCC activity has been demonstrated to be directly related to the
Akt-mediated phosphorylation of the accessory/chaperone subunit
Cavb2a,37,38 which in turn, protects the pore-forming Cava1C
subunit from the proteolytic degradation system.34 This complex
regulation results in a greater density of Cava1C in the plasma mem-
brane and a consequent increase in the open probability of LTCCs.
The recent finding that inhibition of PI3Kg signalling finely modulates
LTCCs by impairing both Cavb2a phosphorylation and Cava1C trans-
location in the plasma membrane of smooth muscle cells12 explains
how PI3Kg is capable of exerting a major role in the establishment
of vascular myogenic tone.
It is also worth emphasizing that we documented that PI3Kg signalling
is crucial not only for Ang II-induced L-type Ca2+ influx but also for oxi-
dative stress,13 thus strengthening the reported common link between
myogenic tone and oxidative stress.39 This evidence also suggests that
the possible role of PI3Kg in regulating the vascular inflammatory re-
sponse induced by high blood pressure requires further exploration.
With regard to how PI3Kg is activated, it is well known that the
g-isoform is activated by the bg subunit of the GPCR. Indeed, stimu-
lation of the Ang II type 1 receptor (AT1R) by Ang II in vascular myo-
cytes has been demonstrated to activate PI3Kg, which, in turn,
regulates LTCCs.7,38
In contrast, more enigmatic is how the perfusion pressure per se,
devoid of neurohormonal signals, can activate a Gbg-dependent
enzyme, such as PI3Kg. Interestingly, it has been recently reviewed
how cellular mechanotransduction of pressure could be mediated by
membrane receptors and associated second messengers.40 On this
issue, it has been shown that the AT1R could be required for mechan-
osensitivity, even in the absence of its ligand, Ang II. The capability of
these receptors to adopt an active conformation, when recruited by a
mechanical stimulus, allows G protein coupling and consequent bg ac-
tivation.40 Thus, it is tempting to speculate that these mechanisms
through AT1R/bg could activate PI3Kg signalling, allowing a fine modu-
lation of myogenic response through regulation of LTCC subunits, in
both a ligand-dependent and a ligand independent manner (Figure 1).
We believe that now a further piece of knowledge has been added
on the signalling pathways activated when the mechanical stress
caused by pressure itself is perceived by the vessel.
4. PI3Kg in pressure-induced target
organ damage
Given the wide expression of PI3Kg in the cardiovascular system and
the fact that the heart is subjected to the continuous challenge of high
406 D. Carnevale and G. Lembo

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Figure 1 PI3Kg signalling in smooth muscle cells. Agonist-induced stimulation of the GPCR in vascular smooth muscle cells activates PI3Kg that, in
turn, regulates, through Akt-dependent phosphorylation of LTCC subunit Cavb2a, translocation of the pore-forming Cava1C subunit in the plasma
membrane and consequent increased LTCC open probability. Perfusion pressure per se can induce the GPCR to adopt an active conformation, when
recruited by a mechanical stimulus, allowing G protein coupling and consequent bg activation that activates PI3Kg signalling to regulate of LTCC
subunits. Abbreviations: a1C and b2 are LTCC subunits; AngII, angiotensin II; bg, Gbg; Go, Golgi complex; GPCR, G-protein coupled receptor;
M, mitochondria; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol trisphosphate; rER, rough endoplasmic reticulum.

blood pressure, here we will review a large body of literature that has,
in the past decade, explored the role of PI3Kg in cardiac remodelling
and heart failure, in the light of the increasing knowledge concerning
the involvement of this signalling in control of blood pressure.
When PI3Kg-null mice were generated, the first evidence that
came to light was that targeted inactivation of this enzyme enhances
in vivo and in vitro contractility of cardiomyocytes in basal conditions,
indicating that PI3Kg is as a negative regulator of cardiac muscle con-
tractility.27 On the contrary, this cardiac phenotype, counterintuitive
as regarding the antihypertensive effect of blocking this signalling,
further emphasizes the major role of vascular PI3Kg signalling in
blood pressure control.
However, when a pressure overload was imposed on the left ven-
tricle, PI3Kg activity was found to be increased in the heart.28 This
finding paved the way for exploration of this signalling in cardiac re-
modelling and heart failure. It is important to note that, as indicated
in a number of studies, GPCR signalling, which is linked to PI3Kg ac-
tivation, plays a crucial role in the compensatory hypertrophic re-
sponse to mechanical overload. On this issue, the hypertrophic
response observed in mice chronically treated with b-adrenergic ago-
nists, accompanied by fibrosis and heart tissue damage, is less pro-
nounced when PI3Kg is absent.29 As a consequence, it could be
envisaged that inhibition of the function of PI3Kg might prevent
cardiac hypertrophy and failure in response to hypertension.
In order to characterize the role of PI3Kg in the heart further,
knock-in mice expressing a kinase-dead PI3Kg (PI3Kg KD) were gener-
ated, allowing disclosure of the contribution of both faces of this
enzyme, namely the kinase dependent and the kinase independent.
Interestingly, while both PI3Kg-null and kinase-dead mice exhibited
an overlapping impairment of the immune response, the kinase-dead
mutant mice did not show enhanced myocardial contractility and
were protected from cardiac damage induced by pressure overload,
which is the converse of what was observed in PI3Kg-null mice.30
In particular, PI3Kg-deficient mice subjected to a short period of
haemodynamic overload showed massive cardiac necrosis, which was
completely absent in PI3Kg KD mice.30 Investigation of cardiac intracel-
lular signalling led to understanding of the different impact of the
absence or the enzymatic inactivation of PI3Kg, in response to pressure
overload. Indeed, while PKB/Akt and, in general, mitogen-activated
protein kinase activation, was not up-regulated in both mutant strains
in response to pressure overload, a different cAMP homeostasis was
observed.30 A previous study had already reported that PI3Kg modu-
lates baseline cAMP levels in isolated cardiomyocytes.27 The generation
of PI3Kg KD mice led to the finding that regulation of cAMP levels are
independent of the kinase activity of PI3Kg, because the elevation of
cAMP levels in PI3Kg-null hearts was dramatically higher both in
basal conditions and in response to pressure overload.30
These results highlighted a dual role of PI3Kg. On the one hand, it
controls mitogen-activated protein kinase and Akt signalling through
its kinase activation and possibly by inducing fibrosis and hypertrophy,
respectively. On the other hand, PI3Kg regulates protein interactions
in a kinase-independent way, and in particular is an essential compo-
nent of a complex controlling phosphodiesterase-mediated cAMP hy-
drolysis, inducing cAMP level reduction, and eventually modulating
cardiac contractility in a negative manner.
More recent studies have further characterized the actions accom-
plished by PI3Kg in the heart, clarifying that it participates in the re-
sponse to adrenergic stimulation of the heart by engaging cAMP
PI3Kg and hypertension 407

and phosphoinositide second messenger signalling cascades, by sus-
taining b-adrenergic receptor internalization through its catalytic func-
tion, and by controlling phosphodiesterase 3B activity via a
kinase-independent mechanism.31 In particular, it has been shown
that PI3Kg anchors protein kinase A, which, in turn, activates
phosphodiesterase 3B to enhance cAMP degradation and phosphory-
lates PI3Kg to inhibit PIP3 production, thus providing a local feedback
control.31
Finally, to better define the translational potential of PI3Kg inhib-
ition in preclinical models of pressure-induced heart failure and to
clarify the cell types involved, we analysed PI3Kg KD mice and bone-
marrow chimeras with bone-marrow-derived cells and hearts of dif-
ferent genotypes subjected to long-term pressure overload.32 With
the use of PI3Kg KD bone-marrow chimeras, we have demonstrated
in experimental models of immune disease.41 45 Furthermore, we
have recently demonstrated a beneficial role of PI3Kg inhibition in
cardiomyopathy caused by pressure overload, in which challenges
for cardiac and inflammatory cells are strictly intertwined.32
Our results identifyied a role for PI3Kg in the regulation of
myogenic tone12 and the hypertensive response to Ang II,13 which
led us to explore the effectiveness of inhibition of this signalling in
hypertension.12 The use of two independent small molecules inhibit-
ing PI3Kg, namely AS605240, which is already commercially available,
and the novel molecule developed in our laboratory, GE21 (patent
pending), allowed us to disclose, for the first time, an unprecedented
antihypertensive effect of the inhibition of kinase-dependent signalling
of PI3Kg,12 which until then had gained increasing attention only as a
promising pharmacological target for the treatment of inflammation

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that inhibition of PI3Kg in both bone-marrow-derived and cardiac and for protection against maladaptive cardiac remodelling. We
cells is required for protection from cardiac dysfunction, indicating further disclosed that the antihypertensive effect of PI3Kg inhibitors
that PI3Kg exerts combined effects in different cell types during the is realized by reducing total peripheral resistance, obtained by coun-
cardiac response to pressure overload and transition towards heart teracting the development of myogenic tone in response to pressure
failure.32 and thus relaxing resistance arteries.12
On the whole, the data obtained with drugs that selectively inhibit
the PI3Kg isoform and the recent genetic evidence in humans that
5. Therapeutic applications of associates PI3Kg with blood pressure regulation strongly support
PI3Kg selective inhibitors: novel the premise that inhibition of this pathway could be considered
antihypertensive? further as a novel tool to fight hypertension and its deleterious
damage in target organs.
The discovery of a central role for PI3Kg in diseases caused by dys-
functional immune responses, whose conventional treatment only
sometimes gives a fairly good control of disease progression and
might have important adverse effects, has led to the development 6. Perspectives
of selective pharmacological inhibitors of this molecular target. In the light of the recently discovered haemodynamic effect of PI3Kg
These diseases include autoimmune disorders, such as systemic inhibition, at least two aspects of potential clinical use should be
lupus erythematosus and rheumatoid arthritis, allergic disorders, re- considered.
spiratory diseases, such as asthma and chronic obstructive pulmonary First, an interesting issue emerges when considering that PI3Kg sig-
disease, and also cardiovascular pathologies whose onset and/or nalling has a well-known role in inflammation, and that inflammation
progression is driven by an inflammatory insult, such as myocardial represents a consistent pathophysiological trait of hypertension-
infarction and atherosclerosis. induced organ damage.46 Thus, the use of PI3Kg inhibitors could be
In the last 10 years, several small molecules targeting PI3Kg have a combined strategy, with beneficial effects for both haemodynamics
been developed by different companies (Table 2) and rapidly explored and inflammation-related organ damage. This seems especially intri-
guing because the use of classical non-steroidal anti-inflammatory
drugs is frequently reported to dampen the blood pressure-lowering
Table 2 PI3Kg selective inhibitors: therapeutic
actions of various antihypertensive medications,47,48 in contrast to
applications in experimental models of diseases
that observed with PI3Kg inhibitors. Therefore, it would be important
Compound Therapeutic Experimental Reference in the future to define the effect of PI3Kg inhibition better in the in-
application models flammatory response accompanying hypertension, in order to validate
....................................................................................
the use of these inhibitors as a double strategy to fight both hyperten-
AS252424/ Inflammatory Systemic lupus 31
sion and hypertension-related inflammation and/or concomitant in-
AS605240 diseases on erythematosus
autoimmune flammatory diseases.
basis The second aspect to be borne in mind is that recent studies iden-
Rheumatoid 30 tify PI3Kg as a new target in atherosclerosis, because it modulates
arthritis multiple stages of plaque formation, such as fatty streak constitution,
Cardiovascular Atherosclerosis 34 cellular composition, and final fibrous cap establishment. In particular,
diseases it has been shown that pharmacological inhibition of PI3Kg alleviates
Myocardial 32,33 atherosclerotic plaque development in two murine models of athero-
infarction
sclerosis, an effect ascribable to loss of PI3Kg function in immune
Heart failure 29
cells.45 Thus, PI3Kg inhibition will allow the treatment of hyperten-
Hypertension 7
sion, which represents one of the main risk factors for atherosclerosis,
GE21 Cardiovascular Hypertension 7
while reducing inflammation in the plaque, offering a unique thera-
diseases
peutic strategy, in comparison to the currently available antihyperten-
sive armamentarium.
408
Acknowledgements
We would like to thank Dr Angelo Maffei for critical reading of the
manuscript and Dr Antonio Damato for technical support.
Conflict of interest: none declared.
Funding
This work was supported by Italian Ministry of Health Ricerca corrente,
Cinquepermille, Ricerca finalizzata 2007, by Sapienza University
Ateneo Federato 2008, and by Fondazione Roma to G.L.
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