Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis
Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis
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DOI：
10.1073/pnas.0702663104
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发表时间：
2007-05-08
影响因子：
11.1
通讯作者：
Cantley, Lewis C.
中科院分区：
文献类型：
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作者：
Chang, James D.;Sukhova, Galina K.;Cantley, Lewis C.
由趋化因子引起的炎性细胞活化需要通过磷酸肌醇3-激酶（PI 3-激酶）和PI 3-激酶依赖性蛋白丝氨酸/苏氨酸激酶Akt的细胞内信号传导。动脉粥样硬化是由氧化修饰的（致动脉粥样硬化的）脂蛋白、趋化因子和激活PI 3-激酶的其他激动剂驱动的慢性炎症过程。在这里，我们表明，巨噬细胞PI 3-激酶/Akt被氧化低密度脂蛋白，炎症趋化因子和血管紧张素II激活。这种活化在缺乏p110 γ（Ib类PI 3-激酶的催化亚基）的巨噬细胞中显著减少或不存在。我们进一步证实了载脂蛋白E（apoE）基因敲除小鼠动脉粥样硬化斑块中巨噬细胞/泡沫细胞PI 3-激酶/Akt的激活，这表明动脉粥样硬化的侵袭性形式，而在缺乏p110 γ的apoE基因敲除小鼠的病变中，尽管存在Ia类PI 3-激酶，但PI 3-激酶/Akt的激活是不可检测的。此外，在研究的所有年龄段，apoE（-/-）p110 gamma（-/-）小鼠中的斑块显著小于apoE（-/-）p110 gamma（+/+）或apoE（-/-）p110 gamma（+/-）小鼠。与缺乏Ia类PI 3-激酶的小鼠中观察到的胚胎致死率形成鲜明对比，p110 γ的种系缺失导致小鼠表现出正常的生存能力、寿命和生育力，先天免疫和炎症反应的耐受性相对较好，这些缺陷可能在动脉粥样硬化和多发性硬化等疾病中发挥作用。我们的研究结果不仅揭示了动脉粥样硬化形成过程中炎症信号的机制，而且进一步确定了p110 γ作为人类动脉粥样硬化性心血管疾病一级和二级预防中药物干预的可能靶点。
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.