Beneficial Effect of Glucose Control on Atherosclerosis Progression in Diabetic ApoE^−/− Mice: Shown by Rage Directed Imaging

Objective. Receptor for advanced glycated endproducts (RAGE) plays an important role in atherogenesis in diabetes. We imaged RAGE to investigate the effect of glucose control to suppress RAGE and reduce atherosclerosis in apolipoprotein E null (apoE^−/−) diabetic mice. Methods and Results. Thirty-three apoE^−/− mice received streptozotocin and 6 weeks later 15 began treatment with insulin implants. Blood glucose measurements during study averaged: 140 ± 23 mg/dL (treated) and 354 ± 14 mg/dL (untreated). After 15 wk 30 mice were injected with Tc99m-anti-RAGE F(ab′)2, 3 with Tc99m-nonimmune IgG F(ab′)2, and all with CT contrast agent and underwent SPECT/CT imaging. At necropsy, the proximal aorta was weighed, counted, and sectioned and the % injected dose per gram (%ID/g) was calculated. From the merged SPECT/CT scans, tracer uptake localized to arteries was lower in the treated mice: 3.15±1.82×10-3 versus 8.69±4.58×10-3%ID (P=0.001). Percent cross-sectional lesion area was smaller in the treated (14.3±7.8% versus 29.5±10.9%) (P=0.03). RAGE uptake on scans (%ID) correlated with quantitative RAGE staining in the atheroma and with %ID/g (R=0.6887; P=0.01). Lesion size as percent cross-sectional area was smaller in the treated (14.3±7.8% versus 29.5±10.9%) (P=0.03). RAGE uptake on scans (%ID) correlated with quantitative RAGE staining in the atheroma and with %ID/g (R=0.6887; P=0.01). Conclusions. These results support the importance of suppressing RAGE to reduce atherosclerotic complications of diabetes and value of molecular imaging to assess treatment effect.