title: Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes.
abstract: 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-gamma (PI3Kgamma) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3Kgamma in the cardiovascular system suggest that PI3Kgamma plays a role in atherosclerosis.
  
  
  RESULTS
  Here, we demonstrate that a specific PI3Kgamma 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, PI3Kgamma levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor-deficient mice transplanted with wild-type or PI3Kgamma-deficient bone marrow demonstrated that functional PI3Kgamma in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3Kgamma activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization.
  
  
  CONCLUSIONS
  These data identify PI3Kgamma 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.
authors.affiliation: INSERM U563, Département Lipoprotéines et Médiateurs Lipidiques, Toulouse-Purpan, BP 3028, 31024 Toulouse Cedex 3, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Fougerat
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gayral
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.forename: Alexia
authors.initials: A
authors.lastname: Schambourg
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückle
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Schwarz
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Salles
authors.forename: Bertrand
authors.initials: B
authors.lastname: Perret
authors.forename: Monique
authors.initials: M
authors.lastname: Breton-Douillon
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Wymann
authors.forename: Muriel
authors.initials: M
authors.lastname: Laffargue
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000071876:Prostaglandin-E Synthases; D011810:Quinoxalines / Q000627:therapeutic use*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D001057:Apolipoproteins E; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D011973:Receptors, LDL; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases