Molecular imaging of atherosclerotic plaques targeted to oxidized LDL receptor LOX-1 by SPECT/CT and magnetic resonance.
BACKGROUND
The oxidized low-density lipoprotein receptor (LDLR) LOX-1 plays a crucial role in atherosclerosis. We sought to detect and assess atherosclerotic plaque in vivo by using single-photon emission computed tomography/computed tomography and magnetic resonance imaging and a molecular probe targeted at LOX-1.


RESULTS
Apolipoprotein E(-/-) mice fed a Western diet and LDLR(-/-) and LDLR(-/-)/LOX-1(-/-) mice fed an atherogenic diet were used. Imaging probes consisted of liposomes decorated with anti-LOX-1 antibodies or nonspecific immunoglobulin G, (111)indium or gadolinium, and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine fluorescence markers. In vivo imaging was performed 24 hours after intravenous injection (150 microL) of LOX-1 or nonspecific immunoglobulin G probes labeled with either (111)indium (600 muCi) or gadolinium (0.075 mmol/kg), followed by aortic excision for phosphor imaging and Sudan IV staining, or fluorescence imaging and hematoxylin/eosin staining. The LOX-1 probe also colocalized with specific cell types, apoptosis, and matrix metalloproteinase-9 expression in frozen aortic sections. Single-photon emission computed tomography/computed tomography imaging of the LOX-1 probe showed aortic arch "hot spots" in apolipoprotein E(-/-) mice (n=8), confirmed by phosphor imaging. Magnetic resonance imaging showed significant Gd enhancement in atherosclerotic plaques in LDLR(-/-) mice with the LOX-1 (n=7) but not with the nonspecific immunoglobulin G (n=5) probe. No signal enhancement was observed in LDLR(-/-)/LOX-1(-/-) mice injected with the LOX-1 probe (n=5). These results were confirmed by ex vivo fluorescence imaging. The LOX-1 probe bound preferentially to the plaque shoulder, a region with vulnerable plaque features, including extensive LOX-1 expression, macrophage accumulation, apoptosis, and matrix metalloproteinase-9 expression.


CONCLUSIONS
LOX-1 can be used as a target for molecular imaging of atherosclerotic plaque in vivo. Furthermore, the LOX-1 imaging signal is associated with markers of rupture-prone atherosclerotic plaque.
Li
Dayuan
D
Cardiovascular Division, University of Virginia, Charlottesville, VA 22908, USA.
Patel
Amit R
AR
Klibanov
Alexander L
AL
Kramer
Christopher M
CM
Ruiz
Mirta
M
Kang
Bum-Yong
BY
Mehta
Jawahar L
JL
Beller
George A
GA
Glover
David K
DK
Meyer
Craig H
CH
D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism*; D005682:Gadolinium; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000737:chemistry; D020287:In Situ Nick-End Labeling; D007205:Indium Radioisotopes; D008081:Liposomes; D008279:Magnetic Resonance Imaging; D051379:Mice; D018613:Microscopy, Confocal; D057054:Molecular Imaging / Q000379:methods*; D019275:Radiopharmaceuticals / Q000494:pharmacology; D051131:Receptors, Oxidized LDL / Q000378:metabolism*; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D013194:Staining and Labeling; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D008081:Liposomes; C495138:Olr1 protein, mouse; D019275:Radiopharmaceuticals; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D005682:Gadolinium