Hematopoietic Akt2 deficiency attenuates the progression of atherosclerosis
Hematopoietic Akt2 deficiency attenuates the progression of atherosclerosis
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DOI：
10.1096/fj.14-262097
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发表时间：
2015-02-01
期刊：
影响因子：
4.8
通讯作者：
Fernandez-Hernando, Carlos
中科院分区：
文献类型：
--
作者：
Rotllan, Noemi;Chamorro-Jorganes, Aranzazu;Fernandez-Hernando, Carlos
动脉粥样硬化是糖尿病和肥胖伴胰岛素抵抗患者死亡和残疾的主要原因。Akt 2是一种磷酸肌醇依赖性丝氨酸-苏氨酸蛋白激酶，在胰岛素敏感组织中高度表达，但其在动脉粥样硬化进展中的作用尚不清楚。因此，我们旨在研究Akt 2在动脉粥样硬化进展过程中的作用。我们发现，尽管有较高的血脂和血糖水平，但生殖系Akt 2缺陷小鼠与野生型小鼠形成相似的动脉粥样硬化斑块。值得注意的是，与移植野生型骨髓细胞的Ldlr（-/-）小鼠相比，将从Akt 2（-/-）小鼠分离的骨髓细胞移植到Ldlr（-/-）小鼠导致动脉粥样硬化进展的显著减少。体外研究表明，Akt 2是响应致动脉粥样硬化细胞因子（单核细胞趋化蛋白-1和巨噬细胞集落刺激因子）的巨噬细胞迁移所必需的。此外，Akt 2（-/-）巨噬细胞积累较少的胆固醇，并有一个替代激活或M2型表型时，刺激促炎细胞因子。总之，这些结果提供了巨噬细胞Akt 2调节迁移、炎症反应和胆固醇代谢的证据，并表明靶向巨噬细胞中的Akt 2可能有利于治疗动脉粥样硬化。
Atherosclerosis is the major cause of death and disability in diabetic and obese subjects with insulin resistance. Akt2, a phosphoinositide-dependent serine-threonine protein kinase, is highly express in insulin-responsive tissues; however, its role during the progression of atherosclerosis remains unknown. Thus, we aimed to investigate the contribution of Akt2 during the progression of atherosclerosis. Wefound that germ-line Akt2 deficient mice develop similar atherosclerotic plaques as wild-type mice despite higher plasma lipids and glucose levels. It is noteworthy that transplantation of bonemarrow cells isolated from Akt2(-/-) mice to Ldlr(-/-) mice results in marked reduction of the progression of atherosclerosis compared with Ldlr(-/-) mice transplanted with wild-type bone marrow cells. In vitro studies indicate that Akt2 is required for macrophage migration in response to proatherogenic cytokines (monocyte chemotactic protein-1 and macrophage colony-stimulating factor). Moreover, Akt2(-/-) macrophages accumulate less cholesterol and have an alternative activated orM2-type phenotype when stimulated with proinflammatory cytokines. Together, these results provide evidence that macrophage Akt2 regulates migration, the inflammatory response and cholesterol metabolism and suggest that targeting Akt2 in macrophages might be beneficial for treating atherosclerosis.