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

ABSTRACT: 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.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.Serial optical molecular imaging demonstrates that plaque MMP and Mac activity in vivo intensify with hypercholesterolemia and are reduced by PIO therapy.

SUBMITTER: Chang K

PROVIDER: S-EPMC3030475 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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

Chang Kiyuk K 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

Arteriosclerosis, thrombosis, and vascular biology 20100805 10

<h4>Objective</h4>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.<h4>Methods and results</h4>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-a ...[more]

PMID: 20689078

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Project description:BackgroundType 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease.MethodsThe MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes.ResultsIn a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1β, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes.ConclusionOur study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets.Trial registrationThe MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).

Dataset Information

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

Publications

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

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