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-γ (PI3Kγ) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3Kγ in the cardiovascular system suggest that PI3Kγ plays a role in atherosclerosis.

Methods and Results— Here, we demonstrate that a specific PI3Kγ 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, PI3Kγ levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor–deficient mice transplanted with wild-type or PI3Kγ-deficient bone marrow demonstrated that functional PI3Kγ in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3Kγ activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization.

Conclusions— These data identify PI3Kγ 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.