Monitoring therapeutical intervention with ezetimibe using targeted near-infrared fluorescence imaging in experimental atherosclerosis.
Ezetimibe (EZE), an inhibitor of cholesterol absorption, reduces atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. The matrix protein ED-B fibronectin (ED-B) is upregulated in atherosclerotic lesions. Using a novel conjugate for near-infrared fluorescence (NIRF) imaging targeting ED-B, we studied the effect of EZE on plaque lesion formation in apoE(-/-) mice. ApoE(-/-) mice received EZE (5 mug/kg/d) or chow up to the age of 4, 6, and 8 months. NIRF imaging of aortic lesions was performed 24 hours after intravenous application ex vivo and in vivo. Plaque lesion formation was analyzed by histology and immunohistochemistry. Aortic lesion formation detected by Sudan staining and NIRF imaging was significantly reduced at 6 and 8 months (p < .001). Plaque areas determined by NIRF imaging significantly correlated with Sudan staining (p < .001). EZE treatment resulted in a significant reduction in plaque macrophage and ED-B immunoreactivity (both p < .05) in brachiocephalic lesions. There was a significant reduction in plaque size in brachiocephalic arteries in 8-month-old mice treated with EZE compared with mice during short-term treatment (p < .05), indicating EZE plaque regression. Targeted NIRF imaging showed a correlation to histologic lesion extension during therapeutical intervention in experimental atherosclerosis.
Graf
Kristof
K
Department of Medicine-Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany. graf@dhzb.de
Dietrich
Thore
T
Tachezy
Michael
M
Scholle
Frank-Detlef
FD
Licha
Kai
K
Stawowy
Philipp
P
Grafe
Michael
M
Hauff
Peter
P
Fleck
Eckart
E
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D001384:Azetidines / Q000627:therapeutic use*; D003952:Diagnostic Imaging / Q000379:methods*; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D000069438:Ezetimibe; D005353:Fibronectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019265:Spectroscopy, Near-Infrared / Q000379:methods*
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D001384:Azetidines; D005353:Fibronectins; D000069438:Ezetimibe