Enzyme-sensitive magnetic resonance imaging targeting myeloperoxidase identifies active inflammation in experimental rabbit atherosclerotic plaques.
BACKGROUND
Inflammation undermines the stability of atherosclerotic plaques, rendering them susceptible to acute rupture, the cataclysmic event that underlies clinical expression of this disease. Myeloperoxidase is a central inflammatory enzyme secreted by activated macrophages and is involved in multiple stages of plaque destabilization and patient outcome. We report here that a unique functional in vivo magnetic resonance agent can visualize myeloperoxidase activity in atherosclerotic plaques in a rabbit model.


RESULTS
We performed magnetic resonance imaging of the thoracic aorta of New Zealand White rabbits fed a cholesterol (n=14) or normal (n=4) diet up to 2 hours after injection of the myeloperoxidase sensor bis-5HT-DTPA(Gd) [MPO(Gd)], the conventional agent DTPA(Gd), or an MPO(Gd) analog, bis-tyr-DTPA(Gd), as controls. Delayed MPO(Gd) images (2 hours after injection) showed focal areas of increased contrast (>2-fold) in diseased wall but not in normal wall (P=0.84) compared with both DTPA(Gd) (n=11; P<0.001) and bis-tyr-DTPA(Gd) (n=3; P<0.05). Biochemical assays confirmed that diseased wall possessed 3-fold elevated myeloperoxidase activity compared with normal wall (P<0.01). Areas detected by MPO(Gd) imaging colocalized and correlated with myeloperoxidase-rich areas infiltrated by macrophages on histopathological evaluations (r=0.91, P<0.0001). Although macrophages were the main source of myeloperoxidase, not all macrophages secreted myeloperoxidase, which suggests that distinct subpopulations contribute differently to atherogenesis and supports our functional approach.


CONCLUSIONS
The present study represents a unique approach in the detection of inflammation in atherosclerotic plaques by examining macrophage function and the activity of an effector enzyme to noninvasively provide both anatomic and functional information in vivo.
Ronald
John A
JA
Robarts Research Institute, London, Ontario, Canada. jronald1@stanfor.edu
Chen
John W
JW
Chen
Yuanxin
Y
Hamilton
Amanda M
AM
Rodriguez
Elisenda
E
Reynolds
Fred
F
Hegele
Robert A
RA
Rogers
Kem A
KA
Querol
Manel
M
Bogdanov
Alexei
A
Weissleder
Ralph
R
Rutt
Brian K
BK
D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000473:pathology; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D019786:Gadolinium DTPA; D006937:Hypercholesterolemia / Q000150:complications; D007249:Inflammation / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009195:Peroxidase / Q000378:metabolism*; D011817:Rabbits; D012044:Regression Analysis
D009195:Peroxidase; D019786:Gadolinium DTPA