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Effect of pioglitazone on inflammation and calcification in atherosclerotic rabbits

An 18F-FDG-PET/CT in vivo imaging study

Wirkung von Pioglitazon auf Entzündung und Verkalkung bei Kaninchen mit Arteriosklerose

Eine 18F-FDG-PET-CT-in-vivo-Bildgebungsstudie

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Abstract

Background

We developed an atherosclerotic rabbit model and tested pioglitazone as a drug intervention for early vascular calcification. Positron emission tomography/computed tomography (PET/CT) was used to evaluate inflammation and therapeutic effects.

Methods

We randomly divided 20 male New Zealand white rabbits into a pioglitazone-treated group (n = 10) and a control group (n = 10). Atherosclerosis was induced via a high-cholesterol diet and endothelial denudation. The animals were maintained on a hyperlipidemic diet for 16 weeks after surgery, and the treatment group received pioglitazone daily. Serum samples were obtained at 8 and 18 weeks postoperatively to assess high-sensitivity C‑reactive protein (hs-CRP) and matrix metalloproteinase-9 (MMP-9) concentrations. Sixteen rabbits underwent a mid-stage PET/CT scan at week 8, and 11 rabbits underwent an end-stage PET/CT scan at week 18. PET/CT parameters, including the mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax), were measured and documented.

Results

There were significantly lower hs-CRP and MMP-9 levels in the pioglitazone group at week 18 (p < 0.01). At the end of the 8th week, no significant between-group differences in SUVmean and SUVmax were observed. From week 8 to week 18, the SUVmean and SUVmax decreased in the pioglitazone group but the SUVmean increased in the control group, with significant between-group differences at the end of the 18th week (p < 0.01). Histopathological examination of aortas in the control and pioglitazone groups revealed significantly smaller plaque area, macrophage density, and tissue calcification area in the latter group.

Conclusion

Pioglitazone affects early vascular microcalcification, and pioglitazone-induced changes can be assessed using 18F-FDG-PET/CT.

Zusammenfassung

Hintergrund

Die Autoren entwickelten ein Kaninchenmodell der Arteriosklerose und testeten Pioglitazon als medikamentöse Intervention bei Gefäßverkalkung im Frühstadium. Zur Beurteilung entzündlicher Veränderungen und therapeutischer Auswirkungen wurde die Positronenemissionstomographie-Computertomographie (PET-CT) eingesetzt.

Methoden

Es wurden 20 männliche weiße Neuseelandkaninchen in eine pioglitazonbehandelte Gruppe (n = 10) und eine Kontrollgruppe (n = 10) eingeteilt. Arteriosklerose wurde durch Gabe von Nahrung mit hohem Cholesteringehalt und endotheliale Denudierung erzeugt. Die Tiere wurden 16 Wochen lang postoperativ bei Gabe hyperlidpidämischer Nahrung gehalten, dabei erhielt die Behandlungsgruppe täglich Pioglitazon. Serumproben wurden sowohl 8 als auch 18 Wochen nach Operation entnommen, um die Konzentration an hochsensitivem C‑reaktivem Protein (hs-CRP) und Matrixmetalloproteinase-9 (MMP-9) zu ermitteln. Bei 16 Kaninchen wurden nach der Hälfte der Untersuchungsdauer in Woche 8 eine PET-CT durchgeführt, bei 11 Kaninchen erfolgte dies zum Ende der Untersuchungsdauer in Woche 18. Dabei wurden PET-CT-Parameter einschließlich des mittleren standardisierten Aufnahmewerts („mean standardized uptake value“, SUVmean) und des maximalen standardisierten Aufnahmewerts („maximum standardized uptake value“, SUVmax) gemessen und dokumentiert.

Ergebnisse

In der Pioglitazongruppe bestanden in Woche 18 signifikant niedrigere hs-CRP- und MMP-9-Werte (p < 0,01) als bei den Kontrollen. Am Ende der 8. Woche fanden sich keine signifikanten Unterschiede bei SUVmean und SUVmax. Von Woche 8 bis Woche 18 nahmen der SUVmean und der SUVmax in der Pioglitazongruppe ab, in der Kontrollgruppe stieg der SUVmean jedoch an, dabei gab es signifikante Unterschiede zwischen den Gruppen am Ende der 18. Woche (p < 0,01). Die histopathologische Untersuchung der Aorten in der Kontroll- und der Pioglitazongruppe zeigte bei Letzterer signifikant kleinere Ausmaße von Plaques, Makrophagendichte und Bereichen mit Gewebeverkalkung.

Schlussfolgerung

Pioglitazon beeinflusst frühe vaskuläre Mikroverkalkungen, und durch Pioglitazon induzierte Veränderungen können mit der 18F-Fluordeoxyglukose(18F-FDG)-PET-CT nachgewiesen werden.

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Funding

This study was supported by the “Twelve Five” National Key Technology R & D Program of China (Grant No. 2011BAI11B05) (http://www.most.gov.cn/eng/programmes1/200610/t20061009_36224.htm), the Beijing Natural Science Foundation of China (Grant No. 7132078) (http://www.bjkw.gov.cn/n244495/index.html) and the National Natural Science Foundation of China (Grant No. 81370437) (https://isisn.nsfc.gov.cn/egrantindex/funcindex/prjsearch-list). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Beijing Anzhen Hospital, Capital Medical University, Anzhen Road, Chaoyang District, 100029, Beijing, China

    J. Xu, M. Nie, M. Zhang, Y. Yan, T. Feng, X. Zhao & Q. Zhao

  2. Affiliated Hospital of Hebei University, Yuhua East Road No. 212, 071000, BaoDing, HeBei, China

    J. Li & Z. Xu

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  1. J. Xu
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Correspondence to Q. Zhao.

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Conflict of interest

J. Xu, M. Nie, J. Li, Z. Xu, M. Zhang, Y. Yan, T. Feng, X. Zhao, and Q. Zhao declare that they have no competing interests.

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Xu, J., Nie, M., Li, J. et al. Effect of pioglitazone on inflammation and calcification in atherosclerotic rabbits. Herz 43, 733–740 (2018). https://doi.org/10.1007/s00059-017-4620-z

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  • DOI: https://doi.org/10.1007/s00059-017-4620-z

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