Loss of 2 Akt (Protein Kinase B) Isoforms in Hematopoietic Cells Diminished Monocyte and Macrophage Survival and Reduces Atherosclerosis in Ldl Receptor-Null Mice
Loss of 2 Akt (Protein Kinase B) Isoforms in Hematopoietic Cells Diminished Monocyte and Macrophage Survival and Reduces Atherosclerosis in Ldl Receptor-Null Mice
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DOI：
10.1161/atvbaha.118.312206
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发表时间：
2019-02-01
影响因子：
8.7
通讯作者：
Linton, MacRae F.
中科院分区：
文献类型：
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作者：
Babaev, Vladimir R.;Ding, Lei;Linton, MacRae F.
目的-巨噬细胞表达3种Akt（蛋白激酶B）亚型，Akt 1，Akt 2和Akt 3，它们显示亚型特异性功能，但在Akt存活信号方面可能是多余的。我们推测巨噬细胞中2种Akt亚型的缺失将抑制它们的生存能力并调节动脉粥样硬化的发展。方法和结果-为了检验这一假设，我们用仅表达Akt 1同种型（仅Akt 1）的双Akt 2/Akt 3敲除造血细胞重建雄性Ldlr（-/-）小鼠。在西方饮食8周后，各组之间的体重和血浆脂质水平没有差异;然而，Akt 1（仅）-> Ldlr（-/-）小鼠比移植有WT（野生型）细胞的对照小鼠发展更小（减少57.6%）的动脉粥样硬化病变，具有更多的凋亡巨噬细胞。接下来，用表达Akt 3同种型（仅Akt 3）的双Akt 1/Akt 2敲除造血细胞重建雄性和雌性Ldlr（-/-）小鼠。雌性和雄性Akt 3（仅）-> Ldlr（-/-）接受者具有比对照WT -> Ldlr（-/-）小鼠显著更小（分别为61%和41%）的病变。与WT细胞相比，造血细胞中2种Akt同种型的缺失导致白色血细胞、B细胞和单核细胞的水平显著降低，单核细胞和腹腔巨噬细胞的活力受损。在响应脂多糖，巨噬细胞与一个单一的Akt亚型表达低水平的炎性细胞因子，然而，Akt 1（仅）巨噬细胞表达高水平的抗凋亡IL 10与WT和Akt 3（仅）细胞相比是不同的。结论：在Ldlr（-/-）小鼠中，造血细胞中两种Akt亚型的丢失，仅保留单一的Akt 1或Akt 3亚型，显著损害单核细胞和巨噬细胞的活力，并减少早期动脉粥样硬化。
Objective- Macrophages express 3 Akt (protein kinase B) isoforms, Akt1, Akt2, and Akt3, which display isoform-specific functions but may be redundant in terms of Akt survival signaling. We hypothesize that loss of 2 Akt isoforms in macrophages will suppress their ability to survive and modulate the development of atherosclerosis. Approach and Results- To test this hypothesis, we reconstituted male Ldlr(-/-) mice with double Akt2/Akt3 knockout hematopoietic cells expressing only the Akt1 isoform (Akt1(only)). There were no differences in body weight and plasma lipid levels between the groups after 8 weeks of the Western diet; however, Akt1(only)-> Ldlr(-/-) mice developed smaller (57.6% reduction) atherosclerotic lesions with more apoptotic macrophages than control mice transplanted with WT (wild type) cells. Next, male and female Ldlr(-/-) mice were reconstituted with double Akt1/Akt2 knockout hematopoietic cells expressing the Akt3 isoform (Akt3(only)). Female and male Akt3(only)-> Ldlr(-/-) recipients had significantly smaller (61% and 41%, respectively) lesions than the control WT -> Ldlr(-/-) mice. Loss of 2 Akt isoforms in hematopoietic cells resulted in markedly diminished levels of white blood cells, B cells, and monocytes and compromised viability of monocytes and peritoneal macrophages compared with WT cells. In response to lipopolysaccharides, macrophages with a single Akt isoform expressed low levels of inflammatory cytokines; however, Akt1(only) macrophages were distinct in expressing high levels of antiapoptotic Il10 compared with WT and Akt3(only) cells. Conclusions- Loss of 2 Akt isoforms in hematopoietic cells, preserving only a single Akt1 or Akt3 isoform, markedly compromises monocyte and macrophage viability and diminishes early atherosclerosis in Ldlr(-/-) mice.