Abstract 481: Athero-metabolic and Inflammatory Alterations Promote In-stent Restenosis in ApolipoproteinE Deficient Rats
Purpose Recently, Apoliprotein E deficient (ApoE-/-) rats have been generated by genetic manipulation, while the bench-to-bedside relevance of this novel model for coronary stenosis research has not been elucidated. Here, we seek to characterize vascular inflammation and in-stent cross-sectional stenosis (ICS) development in the abdominal aorta of ApoE-/- rats.
Methods Trans-abdominal aorta bare-metal stent (Multi-LinkMini Vision, Abbott Vascular Inc., Santa Clara, CA; 2.5 x 8 mm; 12 atm) implantation was performed in ApoE-/- rats (Sigma Aldrich Genetic Engineering, Saint Louis, MO). At 7 and 28 days, quantification of ICS, neointimal (NI) area, injury score and inflammation score was conducted using image analysis software (DISKUS, Hilgers, Königswinter). Blood serum analysis for Interleukin (IL)-6, -8 and -10 and for cholesterol levels was performed.
Results Serum cholesterol levels were elevated in ApoE-/- rats (8.63±1.73mmol/l vs. 1.98±0.55mmol/l; p<0.001) as compared to ApoE+/+ rats. IL-6 and (294.7±80.2pg/ml vs. 187.2±2.8pg/ml; p<0.05) and IL-8/CXCL8 (767.5±127.5pg/ml vs. 342.0±39.7pg/ml; p<0.05) were upregulated, while IL-10/cytokine-synthesis inhibitory factor was downregulated (16.8±1.4pg/ml vs. 90.7±6.5pg/ml; p<0.001) in ApoE-/- rats. After stent implantation, injury scores were similar in all groups. At 7 days, ICS (11.1±1.9% vs. 2.1±0.5%; p<0.01) and NI area (0.59±0.09mm2 vs. 0.075±0.02mm2; p<0.01) was increased as compared to controls; concomitantly, at 28 days, ICS (26.6±3.9% vs. 13.1±1.9%; p<0.001) and NI area (1.47±0.37mm2 vs. 0.54±0.10mm2; p<0.01) were elevated. Furthermore, infiltration by chronic inflammatory cells was increased in ApoE-/- rats at 28 days (456.2±181.4 vs. 108.0±25.9 per high power field; p<0.05).
Conclusions In ApoE-/- rats, cholesterol levels as well as pro-inflammatory IL-6 and -8 are upregulated, while anti-inflammatory IL-10 is downregulated. Concomitantly, ApoE-/- rats develop increased ICS after abdominal stent implantation. This novel small animal model enables the characterization of distinctive molecular and mechanical ICS mechanisms in an atherogenic milieu that, notably, renders disposable any miniaturization of tested stents as opposed to mouse models.
- © 2013 by American Heart Association, Inc.