N reported (18). Akt3 potentially phosphorylates ACAT-1, which initiates ACAT-1 polyubiquitylation and
N reported (18). Akt3 potentially phosphorylates ACAT-1, which initiates ACAT-1 polyubiquitylation and subsequent proteasomal degradation. Akt3 deficiency in macrophages promoted foam cell formation and atherosclerosis in ApoE mice, suggesting that Akt-mediated degradation of ACAT-1 GSK-3α review protects vessel walls from atherosclerosis (18). Within this study, we identified that ARIA negatively regulates PI3KAkt signaling and consequently modulatesVOLUME 290 Quantity 6 FEBRUARY six,3790 JOURNAL OF BIOLOGICAL CHEMISTRYARIA Modifies AtherosclerosisFIGURE 5. Loss of ARIA in bone marrow cells is sufficient to exert anti-atherogenic effects. A, thriving bone marrow transplantation was confirmed by genotyping of bone marrows and tails of recipient mice. B, en face preparation with the aorta stained with oil red-O (ORO). ApoE (ARIA ) mice transplanted with DKO bone marrows IL-17 supplier showed significantly lowered atherosclerosis as compared with handle ApoE mice transplanted with ApoE bone marrows. , p 0.05 and #, NS (n 6 each). In contrast, DKO mice transplanted with ApoE (ARIA ) bone marrow exhibited atherosclerotic lesion related to handle mice. Bar: five mm. C, histology of plaques in the aortic sinus stained with oil red-O or Masson’s trichrome. ApoE (ARIA ) mice transplanted with DKO bone marrows showed significantly reduced oil red-O-positive lipid-rich region as compared with control ApoE mice transplanted with ApoE bone marrows. , p 0.01 (n 6 each). Also, ApoE (ARIA ) mice transplanted with DKO bone marrows showed substantially enhanced collagen content as compared with handle mice. , p 0.01 (n six each and every). In contrast, DKO mice transplanted with ApoE (ARIA ) bone marrows exhibited oil red-O-positive lipid-rich area and collagen content comparable to control mice. #, NS (n 6 every). Bar: 100 m. Error bars in C indicate imply S.E.ACAT-1 expression in macrophages. ARIA-mediated modification of ACAT-1 expression altered foam cell formation, and ARIA mice exhibited important reduction of atherosclerotic lesion formation in vivo. These benefits indicate that ARIA is involved within the physiological andor pathological regulation of ACAT-1 expression in macrophages and therefore modulates their foam cell formation. The protective function of Akt1 in atherosclerosis has also been reported (17). Similar to Akt3-deficient mice, Akt1-deficient mice created severe atherosclerosis and occlusive coronary artery illness. However, in contrast to Akt3, bone marrow transplantation experiments revealed that the vascular origin, but not the macrophage origin, of Akt1 exerts vascular protection against atherosclerosis. Akt1 and Akt3 have various roles in macrophages, presumably due to their unique subcellular localization (18). ARIA negatively regulates PI3K function by escalating membrane association of PTEN (20). Simply because PI3K is an upstream activator of Akt1 and Akt3, ARIA probably modulates their activities in endothelial cells and macrophages. However, analysis of bone marrow chimeric mice demonstrated that macrophage-derived but not vascular-derived ARIA drastically contributes for the progression of atheroscleFEBRUARY six, 2015 VOLUME 290 NUMBERrosis. Though vascular Akt plays a crucial part in protecting blood vessels from atherosclerosis, it remains unclear whether enhancing vascular Akt exerts further protection against atherogenesis. Moreover, loss of ARIA induced a moderate boost in Akt activity of 2-fold in endothelial cells (20); therefore, far more accentuation of A.
