Abstract 15476: Macrophage Adipose Triglyceride Lipase Deficiency Attenuates Atherosclerotic Lesion Development in LDL Receptor Knockout Mice
Objective: Cholesterol accumulation in macrophages is a hallmark in atherogenesis. The effects of triglycerides (TG), however, have not been studied in detail so far. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for the initial step in TG hydrolysis. ATGL knockout (KO) mice exhibit massive TG accumulation in multiple tissues, including macrophages. Thus, we studied the effects of macrophage TG accumulation on atherogenesis by deletion of ATGL in macrophages.
Methods: LDL receptor (LDLr) KO mice were transplanted with bone marrow from ATGL KO (ATGL KO → LDLr KO) or wild-type mice (WT → LDLr KO) and were challenged with Western-type diet for 9 weeks to induce atherosclerosis.
Results: Despite increased lipid accumulation in ATGL KO macrophages, the mean atherosclerotic lesion area in ATGL KO → LDLr KO mice was reduced 43% compared to WT → LDLr KO mice (373±37x103 μm2 vs. 652±40x103 μm2, respectively; p<0.001). The smaller lesion size was associated with a 39% increase in intraplaque apoptosis (WT → LDLr KO 7.1±1.4% ATGL KO → LDLr KO: 11.7±1.5% p=0.049) and ATGL KO macrophages accumulated cleaved poly ADP-ribose polymerase (PARP), indicating an increased apoptosis rate of macrophages deficient for ATGL. In addition, a 39% decrease in white blood cells was observed (WT → LDLr KO: 3.87±0.33x109/L; ATGL KO → LDLr KO: 2.35±0.24x109/L; p=0.010), mainly caused by a 49% decrease in neutrophils (p=0.015) and a 55% decrease in monocytes (p=0.021). The production of the important pro-inflammatory cytokine IL-6 was reduced by 30% in ATGL KO macrophages (WT → LDLr KO: 160±11 pg/mL; ATGL KO → LDLr KO: 112±3 pg/mL; p=0.014) and serum MCP-1 concentrations decreased by 66% (WT → LDLr KO: 220±35 pg/mL; ATGL KO → LDLr KO: 74±19 pg/mL; p=0.001). Moreover, the migratory capacity of ATGL KO macrophages towards MCP-1 was reduced by 56% (p=0.014).
Conclusions: We suggest that the attenuation of atherogenesis in ATGL KO → LDLr KO is due to decreased leukocyte availability for infiltration into the arterial wall and increased intraplaque apoptosis.
- © 2010 by American Heart Association, Inc.