Enhanced Akt3 kinase activity reduces atherosclerosis in hyperlipidemic mice in a gender-dependent manner

Akt3 is one of the three members of the serine/threonine protein kinase B (AKT) family, which regulates multiple cellular processes. We have previously demonstrated that global knockout of Akt3 in mice promotes atherogenesis in a macrophage-dependent manner. Whether enhanced Akt3 kinase activity affects atherogenesis is not known. In this study, we crossed atherosclerosis-prone ApoE^-/- mice with a mouse strain that has enhanced Akt3 kinase activity (Akt3^nmf350) and assessed atherosclerotic lesion formation and the role of macrophages in atherogenesis. Significant reduction in atherosclerotic lesion area and macrophage accumulation in lesions were observed in ApoE^-/-/Akt3^nmf350 mice fed a Western-type diet. Experiments using chimeric ApoE^-/- mice with either ApoE^-/-/Akt3^nmf350 bone marrow or ApoE^-/- bone marrow cells showed that enhanced Akt3 activity specifically in bone marrow-derived cells is atheroprotective. The atheroprotective effect of Akt3^nmf350 was more pronounced in male mice. In line with this result, the release of the pro-inflammatory cytokines IL-6, MCP1, TNF-α, and MIP-1α was reduced by macrophages from male but not female ApoE^-/-/Akt3^nmf350 mice. Levels of IL-6 and TNF-α were also reduced in atherosclerotic lesions of ApoE^-/-/Akt3^nmf350 male mice compared to ApoE^-/- mice. Macrophages from male ApoE^-/-/Akt3^nmf350 mice were also more resistant to apoptosis in vitro and in vivo and tended to have more pronounced M2 polarization in vitro. These findings demonstrated that enhanced Akt3 kinase activity in macrophages protects mice from atherosclerosis in hyperlipidemic mice in a gender-dependent manner.