Abstract 549: Loss of Macrophage Akt2/Akt3 or Akt1/Akt2 Decreases Cell Survival and Suppresses Early Atherosclerosis in Ldlr Null Mice

Abstract

Akt is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes including glucose metabolism and cell survival. Macrophages express three Akt isoforms, Akt1, Akt2 and Akt3 which have been ascribed a number of isoform specific effects but may also be functionally redundant in terms of Akt signaling. Here we hypothesize that dramatic reduction of Akt content with loss of two isoforms will suppress Akt signaling in macrophages, reducing their survival and modulating the development of atherosclerosis. To test this hypothesis, we generated mice with combined deficiency Akt2/Akt3 in hematopoietic cells. Peritoneal macrophages isolated from these mice preserved a similar level of Akt phosphorylation when treated with insulin but exhibited a dramatic increase in apoptosis in response to several different factors that induce ER stress compared to WT or single Akt2 or Akt3 knockout macrophages. Male LDLR null mice reconstituted with double Akt2/Akt3 knockout hematopoietic cells and fed the Western diet for 8 weeks developed smaller (57.6 % reduction) atherosclerotic lesions with more apoptotic macrophages in the proximal aorta than control WT→LDLR -/- mice, in the absence of changes in plasma lipid levels. Thus, loss of Akt2/Akt3 in macrophages increases their sensitivity to apoptosis and decreases atherosclerosis. Next, we generated mice with combined deficiency of Akt1/Akt2 in hematopoietic cells. Again, loss of a single Akt1 or Akt2 isoform in macrophages had no impact on cell apoptosis, whereas combined Akt1/Akt2 deficiency did not change Akt phosphorylation but markedly compromised their sensitivity to different apoptotic stimuli. Furthermore, male and female LDLR -/- mice transplanted with Akt1/Akt2 knockout hematopoietic cells had significantly smaller atherosclerotic lesions with increased macrophage apoptosis than control WT→LDLR -/- mice. Taken together these data indicate that a dramatic reduction of Akt protein in macrophages with loss of either of the Akt1/Akt2 or Akt2/Akt3 pairs of isoforms significantly compromises cell survival and this diminishes early atherosclerosis.