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Loss of 2 Akt (Protein Kinase B) Isoforms in Hematopoietic Cells Diminished
Monocyte and Macrophage Survival and Reduces Atherosclerosis in Ldl
Receptor-Null Mice.

Authors	Babaev VR, Ding L, Zhang Y, May JM, Ramsey SA, Vickers KC, Linton MF
Submitted By	Submitted Externally on 1/25/2019
Status	Published
Journal	Arteriosclerosis, thrombosis, and vascular biology
Year	2019
Date Published	2/1/2019
Volume : Pages	39 : 156 - 169
PubMed Reference	30567482
Abstract	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 (Akt1only). There were no differences in body weight and plasma lipid levels between the groups after 8 weeks of the Western diet; however, Akt1only? 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 (Akt3only). Female and male Akt3only? 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, Akt1only macrophages were distinct in expressing high levels of antiapoptotic Il10 compared with WT and Akt3only 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.

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