Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 19, Pages 8077-8082Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0702663104
Keywords
Akt; inflammation; macrophage; lipoproteins; G protein-coupled receptors
Categories
Funding
- NHLBI NIH HHS [R01 HL080706, R01 HL080706-11, R01 HL080706-10, R01 HL080706-13, R01 HL080706-12] Funding Source: Medline
- NIGMS NIH HHS [GM41890, R01 GM041890, R37 GM041890, R01 GM054597] Funding Source: Medline
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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 p110 gamma, the catalytic subunit of class lb 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 p110 gamma despite the presence of class Ia PI3-kinase. Moreover, plaques were significantly smaller in apoE(-/-)p110 gamma(-/-) mice than in apoE(-/-)p110 gamma(+/+) or apoE(-/-)p110 gamma(+/-)mice at all ages studied. In marked contrast to the embryonic lethality seen in mice lacking class Ia PI3-kinase, germ-line deletion of p110 gamma 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 p110 gamma as a possible target for pharmacological intervention in the primary and secondary prevention of human atherosclerotic cardiovascular disease.
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