Deletion of the phosphoinositide 3-kinase p110gamma gene attenuates murine atherosclerosis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-05, Vol.104 (19), p.8077-8082
• Main Authors: Chang, James D, Sukhova, Galina K, Libby, Peter, Schvartz, Eugenia, Lichtenstein, Alice H, Field, Seth J, Kennedy, Caitlin, Madhavarapu, Swetha, Luo, Ji, Wu, Dianqing, Cantley, Lewis C
• Format: Article
• Language: English
• Subjects: Animals; Apolipoproteins E - physiology; Atherosclerosis - prevention & control; Gene Deletion; Lipoproteins, LDL - pharmacology; Mice; Mice, Inbred C57BL; Oxidative Stress; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - physiology; Proto-Oncogene Proteins c-akt - physiology
• ISSN: 0027-8424

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 p110gamma, 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 p110gamma despite the presence of class Ia PI3-kinase. Moreover, plaques were significantly smaller in apoE-/-p110gamma-/- mice than in apoE-/-p110gamma+/+ or apoE-/-p110gamma+/-mice at all ages studied. In marked contrast to the embryonic lethality seen in mice lacking class Ia PI3-kinase, germ-line deletion of p110gamma 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 p110gamma as a possible target for pharmacological intervention in the primary and secondary prevention of human atherosclerotic cardiovascular disease.