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Submitted on June 8, 2007
Accepted on December 27, 2007

Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase- Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes

Anne Fougerat MSc, Stéphanie Gayral PhD, Pierre Gourdy MD, PhD, Alexia Schambourg MSc, Thomas Rückle PhD, Matthias K. Schwarz PhD, Christian Rommel PhD, Emilio Hirsch PhD, Jean-François Arnal MD, PhD, Jean-Pierre Salles MD, PhD, Bertrand Perret MD, PhD, Monique Breton-Douillon PhD, Matthias P. Wymann PhD, and Muriel Laffargue PhD^*

From INSERM U563, Département Lipoprotéines et Médiateurs Lipidiques, Toulouse, France (A.F., S.G., J.-P.S., B.P., M.B.-D., M.L.); Université Paul Sabatier-Toulouse III, Toulouse, F-31000 France (A.F., S.G., P.G., A.S., J.-F.A., J.-P.S., B.P., M.B.-D., M.L.); CHU Toulouse, Hôpital des Enfants, Unité d’Endocrinologie, Toulouse, F31000 France (J.-P.S.); INSERM U858, Institut de Médecine Moléculaire de Rangueil, Toulouse, France (P.G., A.S., J.-F.A.); CHU Toulouse, Hôpital de Rangueil, Département Explorations fonctionnelles physiologiques, Toulouse, F-31000 France (J.-F.A.); CHU Toulouse, Hôpital de Rangueil, Service Diabétologie-Maladies Métaboliques-Nutrition, Toulouse, F-31000 France (P.G.); CHU Toulouse, Hôpital Purpan, Institut Fédératif de Biologie, Laboratoire de Biochimie, Toulouse, F-31000 France (B.P.); Merck Serono Geneva Research Center, Geneva, Switzerland (T.R., M.K.S., C.R.); University of Turin, Department of Genetics, Biology and Biochemistry, Turin, Italy (E.H.); and Institut of Biochemistry and Genetics, University of Basel, Department of Biomedicine, Basel, Switzerland (M.P.W.).

^* To whom correspondence should be addressed. E-mail: muriel.laffargue{at}toulouse.inserm.fr.

Background—The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase- (PI3K) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3K in the cardiovascular system suggest that PI3K plays a role in atherosclerosis.

Methods and Results—Here, we demonstrate that a specific PI3K inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E–deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor–deficient mice. Furthermore, PI3K levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor–deficient mice transplanted with wild-type or PI3K-deficient bone marrow demonstrated that functional PI3K in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3K activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization.

Conclusions—These data identify PI3K as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment.

Key words: phosphoinositide 3-kinase- • atherosclerosis • inflammation • leukocytes • fibrous cap

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Circulation 2008 117: 1247. [Extract] [Full Text]

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