Pioglitazone Suppresses Inflammation In Vivo in Murine Carotid Atherosclerosis

Abstract

Objective-To investigate the effects of pioglitazone (PIO), a peroxisome proliferator-activated receptor ␥ 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 (PϽ0.05). To assess PIO's effects on plaque inflammation, nondiabetic apolipoprotein E Ϫ/Ϫ 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 (PϽ0.01 versus baseline). In contrast, PIO reduced MMP and Mac target-to-background ratios (PϽ0.01) versus HCD. Changes in MMP and Mac signals correlated strongly (r Ն0.75). Microscopy demonstrated MMP and Mac reductions in PIO-treated mice and a PIO-modulated increase in plaque collagen. Conclusion-Serial optical molecular imaging demonstrates that plaque MMP and Mac activity in vivo intensify with hypercholesterolemia and are reduced by PIO therapy.

Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE −/− Mice

“…Indeed, clinical studies suggest that thin (<65 μm)-capped fibroatheroma is associated with cardiovascular events. 36,37 Some reports show that PPARγ inhibits MMP activity in macrophages, 16,25 but the detailed mechanism has not been clarified. Our results suggest a novel mechanism that PPAR activation inhibits MMP activity, at least in part, by suppressing its inducer, EMMPRIN, in inflammatory macrophages.…”

“…14,15 In an animal study, it was reported that oral administration of pioglitazone reduced macrophage content and matrix metalloproteinase (MMP) activity in murine carotid atherosclerosis. 16 Several clinical studies have also suggested the atheroprotective effects of pioglitazone. [17][18][19] In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive trial), pioglitazone reduced recurrent myocardial infarction in type 2 diabetic patients.…”

Molecular Imaging of the Cardiac Extracellular Matrix

“…In addition to nuclear and magnetic probes, fluorescent peptides have been developed and feasibility of MMP by NIRF imaging evaluated in atherosclerosis. 103,104 Also, a NIRF probe that is activated through proteolytic cleavage by MMP-2 and MMP-9 was used to evaluate MMP activity after MI. 105 Different groups of mice received the probe at different time points after induction of MI, and MMP activity was evaluated by ex vivo NIRF imaging.…”

Pleiotropic Effects of Peroxisome Proliferator-Activated Receptor γ and δ in Vascular Diseases

“…71 Pioglitazone reduces MMP expression and macrophage activity in carotid plaques from ApoE -/-mice, confirming the plaque-stabilizing effect of PPAR γ activation. 72 Such effects are also verified using adenovirus-mediated overexpression of PPAR γ in ApoE -/-mice, including reduced lipid deposition, and reduced macrophage number, increased collagen and SMCs in the plaques, accompanied by decreased MMP-9, tissue factor, MCP-1. 73 Therefore, PPAR γ is atheroprotective during different stages of plaque formation by enhancing cholesterol efflux, reducing macrophage number, reducing extracellular matrix reaction, and stabilizing vulnerable plaques.…”