Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis

Inflammatory cell activation by chemokines requires intracellular signaling through phosphoinositide 3-kinase (PI3-kinase) and the PI3-kinase-dependent protein serine/threonine kinase Akt. Atherosclerosis is a chronic inflammatory process driven by oxidatively modified (atherogenic) lipoproteins, chemokines, and other agonists that activate PI3-kinase. Here we show that macrophage PI3-kinase/Akt is activated by oxidized low-density lipoprotein, inflammatory chemokines, and angiotensin II. This activation is markedly reduced or absent in macrophages lacking p110γ, the catalytic subunit of class Ib PI3-kinase. We further demonstrate activation of macrophage/foam cell PI3-kinase/Akt in atherosclerotic plaques from apolipoprotein E (apoE)-null mice, which manifest an aggressive form of atherosclerosis, whereas activation of PI3-kinase/Akt was undetectable in lesions from apoE-null mice lacking p110γ despite the presence of class Ia PI3-kinase. Moreover, plaques were significantly smaller in apoE −/− p110γ −/− mice than in apoE −/− p110γ +/+ or apoE −/− p110γ +/− mice at all ages studied. In marked contrast to the embryonic lethality seen in mice lacking class Ia PI3-kinase, germ-line deletion of p110γ results in mice that exhibit normal viability, longevity, and fertility, with relatively well tolerated defects in innate immune and inflammatory responses that may play a role in diseases such as atherosclerosis and multiple sclerosis. Our results not only shed mechanistic light on inflammatory signaling during atherogenesis, but further identify p110γ as a possible target for pharmacological intervention in the primary and secondary prevention of human atherosclerotic cardiovascular disease.