Abstract 464: Increased VCAM-1 Expression In Humanized Resistin Double Knock Out Transgenic Mouse

Abstract

Background: Cytokine resistin secreted by human macrophages and mice adipocytes plays a crucial role in atherosclerosis, and chronic inflammation. Our humanized resistin transgenic mouse (TG) model showed that high-fat diet and hyper-resistinemia induced changes in metabolic and inflammatory genes and proteins implicated in atherosclerosis. However, gross arterial atherosclerotic plaque deposition was not detected. Therefore, to better understand the role of resistin on atheroma initiation, we developed the humanized resistin double knock-out-transgenic mouse(hR TG- DKO) model which expresses human resistin without expressing murine resistin and ApoE. Hypothesis: We hypothesize that human resistin enhances early atheroma formation. Methods: Eight- and twelve-week-old TG(n=10), ApoE -/- (n=10), and hR TG- DKO(n=10) mice fed on regular chow. We measured plasma levels of LDL-c with enzymatic assays, and human Resistin with an ELISA assay in the 3 groups. Expression of cell adhesion molecule VCAM-1 in formalin-fixed and paraffin-embedded brachiocephalic arteries was quantified by immunohistochemistry in the 3 groups. All methods were approved by the IACUC at the University of Arizona, Tucson. Data are presented as means ±SEM. Results: Human resistin was detected in the plasma of hR TG- DKO and TG groups with similar levels [6.4±1.5 ng/ml vs 6.3±1.5ng/ml] but was not detected in the plasma of ApoE -/- mice, as expected. LDL-c level was significantly higher in hR TG- DKO and ApoE -/- compared to TG mice respectively [196±17mg/dl vs 26±4mg/dl p=0.0002, 346±25 mg/dl vs 26±4 mg/dl p= 0.0002]. On quantitative analysis, the mean VCAM-1-stained percentage area of brachiocephalic arteries was significantly higher in hR TG- DKO compared to ApoE -/- [4.75%± 1.23 vs 1.77% ± 0.23, p=0.02] and TG mice respectively [4.75%± 1.23 vs 1.33% ± 0.34, p=0.03]. Conclusion: In conclusion, hR TG -DKO exhibits human resistin, high plasma LDL-c level, and increased VCAM-1 expression. Hence, it promotes atherosclerosis initiation, and it is a more appropriate model to study atherosclerosis in the setting of hyper-resistinemia. Further studies are needed to explore the effects of hyper-resistinemia and diet on the progression of atherosclerosis in the hR TG- DKO model.