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.

METHODS AND 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: Anne Fougerat, Stéphanie Gayral, Pierre Gourdy, Alexia Schambourg, Thomas Rückle, Matthias K Schwarz, Christian Rommel, Emilio Hirsch, Jean-François Arnal, Jean-Pierre Salles, Bertrand Perret, Monique Breton-Douillon, Matthias P Wymann, Muriel Laffargue
• Journal: Circulation (Circulation) Vol. 117 Issue 10 Pg. 1310-7 (Mar 11 2008) ISSN: 1524-4539 [Electronic] United States
• PMID: 18268153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
• Apolipoproteins E
• Isoenzymes
• Phosphoinositide-3 Kinase Inhibitors
• Quinoxalines
• Receptors, LDL
• Thiazolidinediones
• Class Ib Phosphatidylinositol 3-Kinase
• PIK3CG protein, human
• Pik3cg protein, mouse
• Intramolecular Oxidoreductases
• Prostaglandin-E Synthases

Topics

• Animals
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (drug therapy)
• Class Ib Phosphatidylinositol 3-Kinase
• Disease Models, Animal
• Humans
• Inflammation (drug therapy)
• Intramolecular Oxidoreductases (deficiency, genetics)
• Isoenzymes (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphoinositide-3 Kinase Inhibitors
• Prostaglandin-E Synthases
• Quinoxalines (therapeutic use)
• Receptors, LDL (deficiency, genetics)
• Thiazolidinediones (therapeutic use)