2012 Carnevale D. PI3K in Hypertension A Novel Therapeutic Target Controlling Vascular Myogenic Tone and Target Organ Damage
2012 Carnevale D. PI3K in Hypertension A Novel Therapeutic Target Controlling Vascular Myogenic Tone and Target Organ Damage
2012 Carnevale D. PI3K in Hypertension A Novel Therapeutic Target Controlling Vascular Myogenic Tone and Target Organ Damage
doi:10.1093/cvr/cvs166
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
* Corresponding author. Tel: +39 0865 929644; fax: +39 0865 927575, Email: [email protected] and [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected].
404 D. Carnevale and G. Lembo
3. PI3Kg in hypertension experimental setting for isolated vessels where the myogenic re-
sponse to perfusion pressure represents the main component of vas-
Since its initial description, the g-isoform of PI3K has been considered cular tone, in the absence of any neurohormonal influence.12 On this
to be almost exclusively expressed by leucocytes.16 Nevertheless, an issue, it is tempting to regard PI3Kg/Akt signalling as one of the main
increasing number of studies in the last decade, prompted by the fact pathways recruited by pressure-induced mechanical stress and strictly
that PI3Kg is the typical isoform activated by GPCRs, and the fact that required for establishment of myogenic tone in response to increases
GPCR signalling is historically recognized as crucial for the modulation in intraluminal pressure in resistance arteries.
of cardiovascular physiology, allowed recognition of a complex Furthermore, our novel data on PI3Kg have added a further piece
pattern of expression that includes the presence of PI3Kg in tissues of knowledge on how this signalling pathway regulates myogenic tone
other than immune cells. Another fascinating aspect that stimulated in resistance arteries, by finely tuning LTCC activity.
the search for roles of PI3Kg outside the immune system was the As stated above, a main role in myogenic vascular contraction is
common relay of environmental stress signals to cells of the cardio- played by calcium influx through LTCCs. Signalling through Akt is of
vascular and immune systems, following a series of intriguingly key importance for the structural organization and functionality of
similar pathways, among which calcium regulation appears to be a re- the LTCC complex at the plasma membrane. In particular, regulation
blood pressure, here we will review a large body of literature that has, an overlapping impairment of the immune response, the kinase-dead
in the past decade, explored the role of PI3Kg in cardiac remodelling mutant mice did not show enhanced myocardial contractility and
and heart failure, in the light of the increasing knowledge concerning were protected from cardiac damage induced by pressure overload,
the involvement of this signalling in control of blood pressure. which is the converse of what was observed in PI3Kg-null mice.30
When PI3Kg-null mice were generated, the first evidence that In particular, PI3Kg-deficient mice subjected to a short period of
came to light was that targeted inactivation of this enzyme enhances haemodynamic overload showed massive cardiac necrosis, which was
in vivo and in vitro contractility of cardiomyocytes in basal conditions, completely absent in PI3Kg KD mice.30 Investigation of cardiac intracel-
indicating that PI3Kg is as a negative regulator of cardiac muscle con- lular signalling led to understanding of the different impact of the
tractility.27 On the contrary, this cardiac phenotype, counterintuitive absence or the enzymatic inactivation of PI3Kg, in response to pressure
as regarding the antihypertensive effect of blocking this signalling, overload. Indeed, while PKB/Akt and, in general, mitogen-activated
further emphasizes the major role of vascular PI3Kg signalling in protein kinase activation, was not up-regulated in both mutant strains
blood pressure control. in response to pressure overload, a different cAMP homeostasis was
However, when a pressure overload was imposed on the left ven- observed.30 A previous study had already reported that PI3Kg modu-
tricle, PI3Kg activity was found to be increased in the heart.28 This lates baseline cAMP levels in isolated cardiomyocytes.27 The generation
finding paved the way for exploration of this signalling in cardiac re- of PI3Kg KD mice led to the finding that regulation of cAMP levels are
modelling and heart failure. It is important to note that, as indicated independent of the kinase activity of PI3Kg, because the elevation of
in a number of studies, GPCR signalling, which is linked to PI3Kg ac- cAMP levels in PI3Kg-null hearts was dramatically higher both in
tivation, plays a crucial role in the compensatory hypertrophic re- basal conditions and in response to pressure overload.30
sponse to mechanical overload. On this issue, the hypertrophic These results highlighted a dual role of PI3Kg. On the one hand, it
response observed in mice chronically treated with b-adrenergic ago- controls mitogen-activated protein kinase and Akt signalling through
nists, accompanied by fibrosis and heart tissue damage, is less pro- its kinase activation and possibly by inducing fibrosis and hypertrophy,
nounced when PI3Kg is absent.29 As a consequence, it could be respectively. On the other hand, PI3Kg regulates protein interactions
envisaged that inhibition of the function of PI3Kg might prevent in a kinase-independent way, and in particular is an essential compo-
cardiac hypertrophy and failure in response to hypertension. nent of a complex controlling phosphodiesterase-mediated cAMP hy-
In order to characterize the role of PI3Kg in the heart further, drolysis, inducing cAMP level reduction, and eventually modulating
knock-in mice expressing a kinase-dead PI3Kg (PI3Kg KD) were gener- cardiac contractility in a negative manner.
ated, allowing disclosure of the contribution of both faces of this More recent studies have further characterized the actions accom-
enzyme, namely the kinase dependent and the kinase independent. plished by PI3Kg in the heart, clarifying that it participates in the re-
Interestingly, while both PI3Kg-null and kinase-dead mice exhibited sponse to adrenergic stimulation of the heart by engaging cAMP
PI3Kg and hypertension 407
and phosphoinositide second messenger signalling cascades, by sus- in experimental models of immune disease.41 45 Furthermore, we
taining b-adrenergic receptor internalization through its catalytic func- have recently demonstrated a beneficial role of PI3Kg inhibition in
tion, and by controlling phosphodiesterase 3B activity via a cardiomyopathy caused by pressure overload, in which challenges
kinase-independent mechanism.31 In particular, it has been shown for cardiac and inflammatory cells are strictly intertwined.32
that PI3Kg anchors protein kinase A, which, in turn, activates Our results identifyied a role for PI3Kg in the regulation of
phosphodiesterase 3B to enhance cAMP degradation and phosphory- myogenic tone12 and the hypertensive response to Ang II,13 which
lates PI3Kg to inhibit PIP3 production, thus providing a local feedback led us to explore the effectiveness of inhibition of this signalling in
control.31 hypertension.12 The use of two independent small molecules inhibit-
Finally, to better define the translational potential of PI3Kg inhib- ing PI3Kg, namely AS605240, which is already commercially available,
ition in preclinical models of pressure-induced heart failure and to and the novel molecule developed in our laboratory, GE21 (patent
clarify the cell types involved, we analysed PI3Kg KD mice and bone- pending), allowed us to disclose, for the first time, an unprecedented
marrow chimeras with bone-marrow-derived cells and hearts of dif- antihypertensive effect of the inhibition of kinase-dependent signalling
ferent genotypes subjected to long-term pressure overload.32 With of PI3Kg,12 which until then had gained increasing attention only as a
the use of PI3Kg KD bone-marrow chimeras, we have demonstrated promising pharmacological target for the treatment of inflammation
24. Rohrschneider LR, Fuller JF, Wolf I, Liu Y, Lucas DM. Structure, function, and biology
Acknowledgements of SHIP proteins. Genes Dev 2000;14:505 520.
We would like to thank Dr Angelo Maffei for critical reading of the 25. House SJ, Potier M, Bisaillon J, Singer HA, Trebak M. The non-excitable smooth
manuscript and Dr Antonio Damato for technical support. muscle: calcium signaling and phenotypic switching during vascular disease. Pflugers
Arch 2008;456:769 785.
26. Suzuki Y, Inoue T, Ra C. L-type Ca2+ channels: a new player in the regulation of Ca2+
Conflict of interest: none declared. signaling, cell activation and cell survival in immune cells. Mol Immunol 2010;47:
640 648.
Funding 27. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T et al. Regulation of
This work was supported by Italian Ministry of Health Ricerca corrente, myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell
2002;110:737 749.
Cinquepermille, Ricerca finalizzata 2007, by Sapienza University
28. Naga Prasad SV, Esposito G, Mao L, Koch WJ, Rockman HA. Gbg-dependent phos-
Ateneo Federato 2008, and by Fondazione Roma to G.L. phoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy.
J Biol Chem 2000;275:4693 4698.
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