Abstract 2: Loss of
Rictor
in Macrophages Suppresses Their Viability and Reduces Atherosclerosis in LDLR Null Mice
The mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that plays a central role in the regulation of cell viability, growth and metabolism. mTOR complex 2 (mTORC2) directly activates phosphorylation of Akt at S 473 , promoting pro-survival signaling. Rictor is an essential component of mTORC2, and genetic loss of Rictor inactivates the complex. To examine whether macrophage mTORC2 signaling has an impact on atherosclerosis, we transplanted male Ldlr null mice with bone marrow isolated from male mice with myeloid-specific Rictor deletion ( Rictor -/- , n=9) and control marrow from Rictor flox-flox mice ( Rictor flox/flox ; n=10). Compared to control mice reconstituted with Rictor flox/flox cells, the recipients of Rictor -/- bone marrow cells exhibited dramatic changes in blood cells including lower levels of white blood cells, B-cells, T-cells and monocytes but had similar levels of neutrophils. After 8 weeks of the Western diet, both groups of recipients had similar levels of body weight, blood glucose, plasma total cholesterol and triglycerides. However, Rictor -/- → Ldlr -/- mice developed smaller atherosclerotic lesions in the proximal and distal aorta (46 and 40% reduction, respectively). These lesions contained less macrophage area and more apoptotic macrophages than lesions of control Rictor flox/flox → Ldlr -/- mice. Importantly, blood monocytes and peritoneal macrophages isolated from Rictor -/- → Ldlr -/- mice were more sensitive to apoptotic stimuli compared to control Rictor flox/flox cells. In response to LPS, Rictor -/- macrophages exhibited the M1 phenotype with high levels of pro-inflammatory gene expression. Both Rictor -/- blood monocytes and macrophages had lower levels of Il10 gene expression than Rictor flox/flox cells. Thus, loss of Rictor and, consequently, mTORC2 in monocyte/macrophages significantly compromises their survival, and this markedly diminishes early atherosclerosis in Ldlr -/- mice. Our results indicate that mTORC2 is a key signaling regulator of macrophage survival and inflammatory responses and promote atherosclerosis.