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Akt Signaling in Macrophage Polarization, Survival, and Atherosclerosis

1
Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232-6300, USA
2
Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232-6300, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(11), 2703; https://doi.org/10.3390/ijms20112703
Received: 10 May 2019 / Revised: 28 May 2019 / Accepted: 29 May 2019 / Published: 1 June 2019
(This article belongs to the Collection Feature Papers in Molecular Biology)
The PI3K/Akt pathway plays a crucial role in the survival, proliferation, and migration of macrophages, which may impact the development of atherosclerosis. Changes in Akt isoforms or modulation of the Akt activity levels in macrophages significantly affect their polarization phenotype and consequently atherosclerosis in mice. Moreover, the activity levels of Akt signaling determine the viability of monocytes/macrophages and their resistance to pro-apoptotic stimuli in atherosclerotic lesions. Therefore, elimination of pro-apoptotic factors as well as factors that antagonize or suppress Akt signaling in macrophages increases cell viability, protecting them from apoptosis, and this markedly accelerates atherosclerosis in mice. In contrast, inhibition of Akt signaling by the ablation of Rictor in myeloid cells, which disrupts mTORC2 assembly, significantly decreases the viability and proliferation of blood monocytes and macrophages with the suppression of atherosclerosis. In addition, monocytes and macrophages exhibit a threshold effect for Akt protein levels in their ability to survive. Ablation of two Akt isoforms, preserving only a single Akt isoform in myeloid cells, markedly compromises monocyte and macrophage viability, inducing monocytopenia and diminishing early atherosclerosis. These recent advances in our understanding of Akt signaling in macrophages in atherosclerosis may have significant relevance in the burgeoning field of cardio-oncology, where PI3K/Akt inhibitors being tested in cancer patients can have significant cardiovascular and metabolic ramifications. View Full-Text
Keywords: atherosclerosis; macrophages; Akt signaling; polarization; apoptosis; survival atherosclerosis; macrophages; Akt signaling; polarization; apoptosis; survival
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Linton, M.F.; Moslehi, J.J.; Babaev, V.R. Akt Signaling in Macrophage Polarization, Survival, and Atherosclerosis. Int. J. Mol. Sci. 2019, 20, 2703.

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