Loss of 2 Akt (Protein Kinase B) Isoforms in Hematopoietic Cells Diminished Monocyte and Macrophage Survival and Reduces Atherosclerosis in Ldl Receptor-Null Mice
Year: 2018
Type: article
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 (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.
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Awards: Vanderbilt Mouse Metabolic Phenotyping Center, Ascorbic Acid Function and Metabolism, Vanderbilt Mouse Metabolic Phenotyping Center, Novel pathways controlling macrophage inflammation and resolution in atherosclerosis, Macrophage Akt and IKKalpha signaling in apoptosis and atherosclerosis, HDL-microRNA Intercellular Communication in Atherosclerosis, Macrophage SR-BI Regulates Autophagy, Angiogenin and tRNA-derived small RNAs, HDL Function in Human Disease
OpenAlex ID: W2906362269