Pioglitazone suppresses inflammation in vivo in murine carotid atherosclerosis: novel detection by dual-target fluorescence molecular imaging.
OBJECTIVE
To investigate the effects of pioglitazone (PIO), a peroxisome proliferator-activated receptor γ agonist, on plaque matrix metalloproteinase (MMP) and macrophage (Mac) responses in vivo in a molecular imaging study.


RESULTS
In vitro, PIO suppressed MMP-9 protein expression in murine peritoneal Macs (P<0.05). To assess PIO's effects on plaque inflammation, nondiabetic apolipoprotein E(-/-) mice receiving a high-cholesterol diet (HCD) were administered an MMP-activatable fluorescence imaging agent and a spectrally distinct Mac-avid fluorescent nanoparticle. After 24 hours, mice underwent survival dual-target intravital fluorescence microscopy of carotid arterial plaques. These mice were then randomized to HCD or HCD plus 0.012% PIO for 8 weeks, followed by a second intravital fluorescence microscopy study of the same carotid plaque. In the HCD group, in vivo MMP and Mac target-to-background ratios increased similarly (P<0.01 versus baseline). In contrast, PIO reduced MMP and Mac target-to-background ratios (P<0.01) versus HCD. Changes in MMP and Mac signals correlated strongly (r ≥0.75). Microscopy demonstrated MMP and Mac reductions in PIO-treated mice and a PIO-modulated increase in plaque collagen.


CONCLUSIONS
Serial optical molecular imaging demonstrates that plaque MMP and Mac activity in vivo intensify with hypercholesterolemia and are reduced by PIO therapy.
Chang
Kiyuk
K
Cardiovascular Research Center and the Cardiology Division, Massachusetts General Hospital, Boston, Mass 02114, USA.
Francis
Sanjeev A
SA
Aikawa
Elena
E
Figueiredo
Jose-Luiz
JL
Kohler
Rainer H
RH
McCarthy
Jason R
JR
Weissleder
Ralph
R
Plutzky
Jorge
J
Jaffer
Farouc A
FA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003094:Collagen / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D061965:Matrix Metalloproteinase Inhibitors; D047495:PPAR gamma; D045162:Thiazolidinediones; D003094:Collagen; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000077205:Pioglitazone