Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes.
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.
Fougerat
Anne
A
INSERM U563, Département Lipoprotéines et Médiateurs Lipidiques, Toulouse-Purpan, BP 3028, 31024 Toulouse Cedex 3, France.
Gayral
Stéphanie
S
Gourdy
Pierre
P
Schambourg
Alexia
A
Rückle
Thomas
T
Schwarz
Matthias K
MK
Rommel
Christian
C
Hirsch
Emilio
E
Arnal
Jean-François
JF
Salles
Jean-Pierre
JP
Perret
Bertrand
B
Breton-Douillon
Monique
M
Wymann
Matthias P
MP
Laffargue
Muriel
M
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*
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