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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >β3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice
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β3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice

机译：β3整合素缺乏促进高脂高脂血症小鼠的动脉粥样硬化和肺部炎症

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摘要

Hyperlipidemia promotes the chronic inflammatory disease atherosclerosis through poorly understood mechanisms. Atherogenic li-poproteins activate platelets, but it is unknown whether platelets contribute to early inflammatory atherosclerotic lesions. To address the role of platelet aggregation in diet-induced vascular disease, we studied β3 integrin-deficient mice (lacking platelet integrin αllbβ3 and the widely expressed nonplatelet integrin αvβ3) in two models of atherosclerosis, apolipoprotein E (apoE)-null and low-density li-poprotein receptor (LDLR)-null mice. Unexpectedly, a high-fat, Western-type (but not a low-fat) diet caused death in two-thirds of the β3~(-/-)apoE~(-/-) and half of the β3~(-/-)LDLR~(-/-) mice due to noninfec-tious pneumonitis. In animals from both models surviving high-fat feeding, pneumonitis was absent, but aortic atherosclerosis was 2- to 6-fold greater in β3~(-/-) compared with β~(+/+) littermates. Expression of CD36, CD40L, and CD40 was increased in lungs of β3~(-/-)LDLR~(-/-) mice. Each was also increased in smooth muscle cells cultured from β3-deficient mice and suppressed by retroviral reconstitution of β3. These data show that the platelet defect caused by αllbβ3 deficiency does not impair atherosclerotic lesion initiation. They also suggest that αvβ3 has a suppressive effect on inflammation, the loss of which induces atherogenic mediators that are amplified by diet-induced hyperlipidemia.
机译：高血脂症通过不充分了解的机制促进慢性炎症性疾病的动脉粥样硬化。致动脉粥样硬化性脂蛋白激活血小板，但血小板是否有助于早期炎症性动脉粥样硬化病变尚不清楚。为了解决血小板聚集在饮食诱发的血管疾病中的作用，我们在两种动脉粥样硬化模型中，即载脂蛋白E（apoE）-无效和低胆固醇血症的低模型小鼠中，研究了β3整合素缺陷型小鼠（缺乏血小板整合素αllbβ3和广泛表达的非血小板整合素αvβ3）。密度脂蛋白受体（LDLR）无效的小鼠。出乎意料的是，高脂，西式（而非低脂）饮食导致三分之三的β3〜（-/-）apoE〜（-/-）死亡，一半的β3〜（-// -）LDLR〜（-/-）小鼠因非感染性肺炎引起。在这两种模型中，高脂喂养后仍存活的动物中不存在肺炎，但与β〜（+ / +）同窝仔相比，β3〜（-/-）的主动脉粥样硬化高出2至6倍。 β3〜（-/-）LDLR〜（-/-）小鼠肺中CD36，CD40L和CD40的表达增加。在缺乏β3的小鼠中培养的平滑肌细胞中的每一种也都增加了，并且被逆转录病毒重建的β3抑制了。这些数据表明，由α11bβ3缺乏引起的血小板缺陷不会损害动脉粥样硬化病变的开始。他们还表明，αvβ3对炎症具有抑制作用，炎症的丧失会诱导致动脉粥样硬化的介质，而饮食诱导的高脂血症会加剧这种介质。

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