Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice.

Babaev VR, Hebron KE, Wiese CB, Toth CL, Ding L, Zhang Y, May JM, Fazio S, Vickers KC, Linton MF
J Lipid Res. 2014 55 (11): 2296-308

PMID: 25240046 · PMCID: PMC4617132 · DOI:10.1194/jlr.M050633

Macrophages play crucial roles in the formation of atherosclerotic lesions. Akt, a serine/threonine protein kinase B, is vital for cell proliferation, migration, and survival. Macrophages express three Akt isoforms, Akt1, Akt2, and Akt3, but the roles of Akt1 and Akt2 in atherosclerosis in vivo remain unclear. To dissect the impact of macrophage Akt1 and Akt2 on early atherosclerosis, we generated mice with hematopoietic deficiency of Akt1 or Akt2. After 8 weeks on Western diet, Ldlr(-/-) mice reconstituted with Akt1(-/-) fetal liver cells (Akt1(-/-)→Ldlr(-/-)) had similar atherosclerotic lesion areas compared with control mice transplanted with WT cells (WT→Ldlr(-/-)). In contrast, Akt2(-/-)→Ldlr(-/-) mice had dramatically reduced atherosclerotic lesions compared with WT→Ldlr(-/-) mice of both genders. Similarly, in the setting of advanced atherosclerotic lesions, Akt2(-/-)→Ldlr(-/-) mice had smaller aortic lesions compared with WT→Ldlr(-/-) and Akt1(-/-)→Ldlr(-/-) mice. Importantly, Akt2(-/-)→Ldlr(-/-) mice had reduced numbers of proinflammatory blood monocytes expressing Ly-6C(hi) and chemokine C-C motif receptor 2. Peritoneal macrophages isolated from Akt2(-/-) mice were skewed toward an M2 phenotype and showed decreased expression of proinflammatory genes and reduced cell migration. Our data demonstrate that loss of Akt2 suppresses the ability of macrophages to undergo M1 polarization reducing both early and advanced atherosclerosis.

Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (18)

Animals Antigens, Ly Atherosclerosis Cell Movement Female Gene Expression Regulation Gene Knockout Techniques Hematopoiesis Macrophages Male Mice Mice, Inbred C57BL Mice, Knockout Monocytes Phenotype Proto-Oncogene Proteins c-akt Receptors, CCR2 Receptors, LDL

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