Pioglitazone suppresses inflammation in vivo in murine carotid atherosclerosis: novel detection by dual-target fluorescence molecular imaging.

Abstract

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.

METHODS AND 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.

• Authors: Kiyuk Chang, Sanjeev A Francis, Elena Aikawa, Jose-Luiz Figueiredo, Rainer H Kohler, Jason R McCarthy, Ralph Weissleder, Jorge Plutzky, Farouc A Jaffer
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 10 Pg. 1933-9 (Oct 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20689078 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Apolipoproteins E
• Cholesterol, Dietary
• Matrix Metalloproteinase Inhibitors
• PPAR gamma
• Thiazolidinediones
• Collagen
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Pioglitazone

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apolipoproteins E (deficiency, genetics)
• Carotid Artery Diseases (drug therapy, pathology, physiopathology)
• Cholesterol, Dietary (administration & dosage)
• Collagen (metabolism)
• Female
• Inflammation (drug therapy, pathology, physiopathology)
• Macrophages (drug effects, pathology)
• Matrix Metalloproteinase 9
• Matrix Metalloproteinase Inhibitors
• Mice
• Mice, Knockout
• Microscopy, Fluorescence
• PPAR gamma (agonists)
• Pioglitazone
• Thiazolidinediones (pharmacology)