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Deletion of the phosphoinositide 3-kinase p110gamma gene attenuates murine atherosclerosis.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2007 May 08; Vol. 104 (19), pp. 8077-82. Date of Electronic Publication: 2007 May 02. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- Animals
Apolipoproteins E physiology
Gene Deletion
Lipoproteins, LDL pharmacology
Mice
Mice, Inbred C57BL
Oxidative Stress
Phosphatidylinositol 3-Kinases genetics
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins c-akt physiology
Atherosclerosis prevention & control
Phosphatidylinositol 3-Kinases physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 104
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 17483449
- Full Text :
- https://doi.org/10.1073/pnas.0702663104