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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #213083
Title: Deletion of the phosphoinositide 3-Kinase p110(gamma) gene attenuates murine atherosclerosis

Author
item CHANG, JAMES - BRIGHAM & WOMEN'S HOSP.
item SUKHOVA, GALINA - BRIGHAM & WOMEN'S HOSP.
item LIBBY, PETER - BRIGHAM & WOMEN'S HOSP.
item SCHVARTZ, EUGENIA - BRIGHAM & WOMEN'S HOSP.
item Lichtenstein, Alice
item FIELD, SETH - MA GENERAL HOSPITAL
item KENNEDY, CAITLIN - BETH ISREAL MED CTR
item MADHAVARAPU, SWETHA - BETH ISREAL MED CTR
item LUO, JI - HARVARD MED SCHOOL
item WU, DIANQING - UNIV OF CONN. HELTH CTR
item CANTLEY, LEWIS - HARVARD MED SCHOOL

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/21/2007
Publication Date: 5/8/2007
Citation: Chang, J., Sukhova, G., Libby, P., Schvartz, E., Lichtenstein, A.H., Field, S., Kennedy, C., Madhavarapu, S., Luo, J., Wu, D., Cantley, L. 2007. Deletion of the phosphoinositide 3-Kinase p110(gamma)gene attenuates murine atherosclerosis. Proceedings of the National Academy of Sciences. 104:19.

Interpretive Summary: Chronic inflammation is thought to play a major role in atherosclerotic lesion formation. The regulatory control over this inflammatory process at a molecular level is not well understood. One driver of this process is oxidatively modified (atherogenic, heart disease promoting) lipoproteins and other compounds that activate the inflammatory process. The current work demonstrates that one potential factor, termed macrophage PI3-kinase/Akt, is activated by multiple factors, including oxidized low-density lipoprotein, inflammatory chemokines, and angiotensin II. This activation was 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. These results shed mechanistic light on inflammatory signaling during atherogenesis, but further identify p110gamma as a possible target for intervention in the primary and secondary prevention of human atherosclerotic cardiovascular disease.

Technical 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.