Abstract 423: Ablation of Insulin-Regulated Aminopeptidase (IRAP/AT4R) Attenuates Lipid Accumulation and Inhibits Plaque Rupture in the Carotid Artery of ApoE Deficient Mice
Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of plasminogen activators, and considerably contributes to matrix turnover, cellular migration, and plaque stability. IRAP, a receptor for angiotensin IV (AngIV), colocalizes with GLUT4 and translocates to cell surface in response to insulin in adipocytes and fibroblasts. Although genetic ablation of IRAP leads to hyperfibrinolysis via PAI-1 downregulation and reduced glucose uptake in muscles and adipose tissues, the potential effects of AngIV-IRAP axis on plaque progression and stability remain unknown. We investigated the process of atherogenesis in a novel plaque rupture model using IRAP and/or ApoE deficient mice (ApoE KO and IRAP/ApoE DKO).
[Methods and Results] in vitro Aortic smooth muscle cells from IRAP-deleted mice had lower expression levels of collagen I and MMP-2, and higher levels in TGFβ, Smad2 and Smad3 if compared to ApoE KO after 10−6 M AngII treatment. The levels of inflammatory markers (MCP-I, IL-6, and TNFα) were comparable between 2 mice. in vivo Mice (age 9weeks, n=12 to 14) fed a normal chow received cuff placement 4 weeks after the ligature of right carotid artery. The samples were excised after 1 week of cuff placement. Although no difference was observed in body weight and epididymal fat weight between 2 groups, the serum cholesterol levels were lower in IRAP/ApoE DKO than ApoE KO (531±78 vs. 326±68 mg/dL, mean±SD, P=0.007), which was accompanied with smaller size in epididymal adipocytes. Plasma active PAI-1 antigen levels were also reduced in IRAP/ApoE DKO (25.1±6.4 vs. 4.92±1.0 ng/mL, P=0.034). IRAP/ApoE DKO had less atherosclerotic lesions in either area of plaque (325±34 vs. 112±18 μm2, P=0.0047) and lipid pool (22.5±2.3 vs. 15.7±1.8 μm2, P=0.037). Despite unaffected macropharge content (CD68: 12.5% vs. 11.8%, P=NS), we did find a reduction of collagen content (picrosirius red. 12.4% vs. 7.7%, P=0.025) and thrombus occlusion with rupture (93.7% vs 60.0%, P=0.038) in the sections of IRAP/ApoE DKO.
[Conclusions] Ablation of IRAP attenuates lipid accumulation in the plaque area and inhibited plaque rupture in ApoE KO, partly due to lower cholesterol level and reduced matrix turnover, suggesting a novel linkage between angiotensin signaling and atherogenesis.