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(Circulation. 2008;117:1310-1317.)
© 2008 American Heart Association, Inc.

Vascular Medicine

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; 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.).

Correspondence to Muriel Laffargue, INSERM U563, Département Lipoprotéines et Médiateurs Lipidiques, Toulouse-Purpan, BP 3028, 31024 Toulouse Cedex 3, France. E-mail muriel.laffargue{at}toulouse.inserm.fr

Received June 8, 2007; accepted December 27, 2007.

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.

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CLINICAL PERSPECTIVE

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