Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis
Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis
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DOI：
10.1016/j.cmet.2006.02.010
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发表时间：
2006-04-01
期刊：
影响因子：
29
通讯作者：
Brüning, JC
中科院分区：
文献类型：
--
作者：
Baumgartl, J;Baudler, S;Brüning, JC
炎症过程在血管疾病的发病机制中起重要作用，胰岛素抵抗型2型糖尿病是动脉粥样硬化发展的重要危险因素。为了直接解决髓系细胞中胰岛素抵抗在动脉粥样硬化发展中的作用，我们创造了髓系特异性胰岛素受体基因失活的小鼠。在apoe缺乏的背景下，MphIRKO小鼠出现较小的动脉粥样硬化病变。巨噬细胞存在自主胰岛素抵抗时，lps刺激的IL-6和IL-1 β表达显著降低。在ApoE缺乏的背景下，胰岛素抵抗的IRS-2缺陷小鼠显示动脉粥样硬化加重，而胚胎肝细胞移植IRS-2(-/-)ApoE（-/-）细胞可改善ApoE缺乏小鼠的动脉粥样硬化。因此，系统性和髓细胞限制性胰岛素抵抗对动脉粥样硬化的发展有相反的影响，提供了直接证据，证明髓细胞谱系自主胰岛素信号提供促炎症信号，易导致动脉粥样硬化的发展。
Inflammatory processes play an important role in the pathogenesis of vascular diseases, and insufin-resistant diabetes mellitus type 2 represents an important risk factor for the development of atherosclerosis. To directly address the role of insulin resistance in myeloid lineage cells in the development of atherosclerosis, we have created mice with myeloid lineage-specific inactivation of the insulin receptor gene. On an ApoE-deficient background, MphIRKO mice developed smaller atherosclerotic lesions. There was a dramatic decrease in LPS-stimulated IL-6 and IL-1 beta expression in the presence of macrophage autonomous insulin resistance. Consistently, while insulin-resistant IRS-2-deficient mice on an ApoE-deficient background display aggravated atherosclerosis, fetal liver cell transplantation of IRS-2(-/-)ApoE(-/-) cells ameliorated atherosclerosis in Apo-E-deficient mice. Thus, systemic versus myeloid cell-restricted insulin resistance has opposing effects on the development of atherosclerosis, providing direct evidence that myeloid lineage autonomous insulin signaling provides proinflammatory signals predisposing to the development of atherosclerosis.