Deletion of the phosphoinositide 3-kinase p110gamma 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 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.
Chang
James D
JD
Beth Israel Deaconess Medical Center (Signal Transduction and Cardiovascular Divisions), Boston, MA 02115, USA.
Sukhova
Galina K
GK
Libby
Peter
P
Schvartz
Eugenia
E
Lichtenstein
Alice H
AH
Field
Seth J
SJ
Kennedy
Caitlin
C
Madhavarapu
Swetha
S
Luo
Ji
J
Wu
Dianqing
D
Cantley
Lewis C
LC
D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000517:prevention & control*; D017353:Gene Deletion; D008077:Lipoproteins, LDL / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology
D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C099252:oxidized low density lipoprotein