Abstract 15417: Macrophage Deficiency of Akt2 or Both Akt1 and Akt2 Reduces Atherosclerosis: Akt is Critical for Macrophage Polarization and Survival
Macrophage phenotype and survival play crucial roles in atherosclerosis. Akt, a serine/threonine protein kinase B, is vital for macrophage activation and survival. Macrophages express three Akt isoforms including Akt1, Akt2 and Akt3 but the roles of the major isoforms, Akt1 and Akt2, in cell activation, survival and atherosclerosis remain unclear. To dissect the impact of macrophage Akt1 and Akt2 isoforms on early atherosclerosis, fetal liver cell transplantation was used to generate mice with hematopoietic deficiency of Akt1, Akt2, or both. LDLR null mice reconstituted with Akt1-/- hematopoietic cells (Akt1-/-→LDLR-/-) had similar atherosclerotic lesion areas compared to control WT→LDLR-/- mice. In contrast, Akt2-/-→LDLR-/- mice had dramatically reduced (69%) atherosclerotic lesions compared to control WT→LDLR-/- mice. Akt2-/- peritoneal macrophages were skewed toward an M2 phenotype and showed restricted ability for M1 priming with diminished expression levels of pro-inflammatory genes and chemokine C-C motif receptor 2 (CCR2). Remarkable, loss of macrophage Akt1 or Akt2 individually had no impact on Akt phosphorylation or apoptosis. In contrast, combined Akt1/Akt2 deficiency markedly reduced (~26% of total) Akt protein levels in macrophages and this augmented cell sensitivity to apoptotic stimuli. Furthermore, male and female LDLR-/- mice reconstituted with double Akt1/Akt2 knockout hematopoietic cells had significantly increased macrophage apoptosis and smaller atherosclerotic lesions than control WT→LDLR-/- mice. Akt2 deficiency suppresses the ability of macrophages for M1 polarization and CCR2 expression, reducing early atherosclerosis in LDLR-/- mice. Loss of both Akt1 and Akt2 in macrophages reduces total Akt protein levels, compromises macrophage survival, and diminishes early atherosclerosis in LDLR-/- mice. Together, our results demonstrate the crucial importance of Akt isoforms in macrophage polarization and Akt protein levels in macrophage survival, both of which critically impact the development of early atherogenesis.
- © 2013 by American Heart Association, Inc.