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

Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1933-9. doi: 10.1161/ATVBAHA.110.206342. Epub 2010 Aug 5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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