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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis
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Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis

机译：磷酸肌醇3-激酶p110γ基因的缺失减弱了鼠的动脉粥样硬化

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摘要

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 p110γ, 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 p110γ despite the presence of class Ⅰa PI3-kinase. Moreover, plaques were significantly smaller in apoE~(-/-) p110γ~(-/-) mice than in apoE~(-/-)p110γ~(+/+) or apoE~(-/-)p110γ~(+/-) mice at all ages studied. In marked contrast to the embryonic lethality seen in mice lacking class Ⅰa PI3-kinase, germ-line deletion of p110γ 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 p110γ as a possible target for pharmacological intervention in the primary and secondary prevention of human atherosclerotic cardiovascular disease.
机译：趋化因子激活炎症细胞需要通过磷酸肌醇3激酶（PI3激酶）和PI3激酶依赖性蛋白丝氨酸/苏氨酸激酶Akt进行细胞内信号传导。动脉粥样硬化是一种慢性炎症过程，由氧化修饰的（动脉粥样硬化）脂蛋白，趋化因子和其他激活PI3激酶的激动剂驱动。在这里，我们表明巨噬细胞PI3-激酶/ Akt被氧化的低密度脂蛋白，炎症趋化因子和血管紧张素Ⅱ激活。在缺乏p110γ（Ⅰb类PI3激酶的催化亚基）的巨噬细胞中，这种活化显着减少或不存在。我们进一步证明了从载脂蛋白E（apoE）-空小鼠的动脉粥样硬化斑块中巨噬细胞/泡沫细胞PI3-激酶/ Akt的激活，这表现出一种攻击性形式的动脉粥样硬化，而在从apoE-尽管存在Ⅰa类PI3激酶，但无p110γ的空小鼠。此外，apoE〜（-/-）p110γ〜（-/-）小鼠的斑块明显小于apoE〜（-/-）p110γ〜（+ / +）或apoE〜（-/-）p110γ〜（+）小鼠/-）研究了所有年龄段的小鼠。与缺乏Ⅰa类PI3激酶的小鼠的胚胎致死力形成鲜明对比的是，p110γ的种系缺失导致小鼠表现出正常的生存能力，寿命和繁殖力，并且对天然免疫和炎症反应的耐受性相对较好，可能会发挥作用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的炎症信号传导机制，而且进一步确定了p110γ作为药物干预人类动脉粥样硬化性心血管疾病的一级和二级预防的可能靶标。

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