JCJC SVSE 1 - JCJC - SVSE 1 - Physiologie, physiopathologie, santé publique

Phosphoinositide -3 kinase gamma in arterial diseases: a promising target – PIKinART

Submission summary

Arterial reconstruction procedures, including balloon angioplasty, stenting and coronary artery bypass, are used to restore blood flow to atherosclerotic arteries. However, restenosis of arteries is a major limitation following application of these procedures, especially in the case of balloon angioplasty with stent placement. Post-angioplasty restenosis is a result of two major processes: neointimal formation and constrictive remodelling. Like the development of atherosclerosis, inflammatory processes are in part responsible for this phenomenon and lead to phenotypic modulation of smooth muscle cells (SMC), resulting in SMC migration and proliferation. In 2002, clinical introduction of drug delivery stents (DES), which inhibit restenotic SMC proliferation and neointimal hyperplasia by the release of anti-proliferative agents, revolutionized interventional cardiology owing to their pronounced ability to reduce restenosis when compared to that of bare-metal stents. However, there are increasing concerns regarding the initiation of endothelial dysfunction and late in-stent thrombosis by the drugs currently used. Thus, alternative specific targets need to be identified. In this context, we are interested in the function of a specific isoform of the phosphoinositide 3-kinase (PI3K) family: the PI3Kgamma. This protein belongs to the class I PI3K family, the only class of PI3K able to produce phosphatidylinositol (3,4,5)-trisphosphate (PIP3) which is involved in a large range of biological processes. Generation of PI3Kgamma-deficient mice demonstrated that this kinase plays a key role in several immune cells such as monocytes and lymphocytes leading to further investigation of PI3K in inflammatory diseases. Recent studies indicate that there are low yet significant levels of PI3Kgamma in the cardiovascular system. Moreover, the generation of mice expressing a catalytically inactive form of PI3Kgamma showed that PI3Kgamma also has kinase-independent effects and can act as a docking protein recruiting phosphodiesterases and modulating cAMP levels in cells. Our team recently showed that PI3Kgamma was essential for inflammatory processes in the arterial wall during atherogenesis and that it drives SMC migration. These data led us to hypothesize that PI3Kgamma could control inflammatory and fibroproliferative mechanisms, two common processes of atherogenesis and in-stent restenosis. In our laboratory we have developed a model of endovascular arterial lesion and, using the original model of mutant PI3Kgamma mice, we demonstrated that modulation of PI3Kgamma activity decreased intimal hyperplasia in vivo. This project proposes now: 1) to determine the cellular mechanisms involved and, more precisely, to compare in vivo a) the role of PI3Kgamma in immune function versus vascular function and b) the kinase-dependent versus kinase-independent roles of PI3Kgamma; 2) to define the kinase dependent role of PI3Kgamma in T cells during intimal hyperplasia; 3) to investigate the kinase-independent function of PI3Kgamma in aortic SMC; 4) to validate PI3Kgamma as a pharmacological target in the prevention of in-stent restenosis in mice and in a preclinical swine model. We expect that this work will provide substantial evidence that PI3Kgamma is a credible drug target in the treatment of vascular diseases.

Project coordination

Muriel LAFFARGUE (UMR1048, Institut des maladies métaboliques et cardiovasculaires) – muriel.laffargue@inserm.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


INSERM UMR1048, Institut des maladies métaboliques et cardiovasculaires

Help of the ANR 199,478 euros
Beginning and duration of the scientific project: December 2012 - 36 Months

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