open access

https://hdl.handle.net/2115/55340

Suppressive Effects of Irbesartan on Inflammation and Apoptosis in Atherosclerotic Plaques of apoE(-/-) Mice: Molecular Imaging with C-14-FDG and Tc-99m-Annexin A5

英語

2014-02-19

PLOS

Plos one

9(2)

e89338

Objectives: To investigate the effects of irbesartan on inflammation and apoptosis in atherosclerotic plaques by histochemical examination and molecular imaging using C-14-FDG and Tc-99m-annexin A5. Background: Irbesartan has a peroxisome proliferator-activated receptor gamma (PPAR gamma) activation property in addition to its ability to block the AT1 receptor. Accordingly, irbesartan may exert further anti-inflammatory and anti-apoptotic effects in atherosclerotic plaques. However, such effects of irbesartan have not been fully investigated. Molecular imaging using F-18-FDG and Tc-99m-annexin A5 is useful for evaluating inflammation and apoptosis in atherosclerotic plaques. Methods: Female apoE(-/-) mice were treated with irbesartan-mixed (50 mg/kg/day) or irbesartan-free (control) diet for 12 weeks (n = 11/group). One week after the treatment, the mice were co-injected with C-14-FDG and Tc-99m-annexin A5, and cryostat sections of the aortic root were prepared. Histochemical examination with Movat's pentachrome (plaque size), Oil Red O (lipid deposition), Mac-2 (macrophage infiltration), and TUNEL (apoptosis) stainings were performed. Dual-tracer autoradiography was carried out to evaluate the levels of C-14-FDG and Tc-99m-annexin A5 in plaques (% IDxkg). In vitro experiments were performed to investigate the mechanism underlying the effects. Results: Histological examination indicated that irbesartan treatment significantly reduced plaque size (to 56.4% +/- 11.1% of control), intra-plaque lipid deposition (53.6%+/- 20.2%) and macrophage infiltration (61.9% +/- 20.8%) levels, and the number of apoptotic cells (14.5%+/- 16.6%). C-14-FDG (43.0% +/- 18.6%) and Tc-99m-annexin A5 levels (45.9% +/- 16.8%) were also significantly reduced by irbesartan treatment. Irbesartan significantly suppressed MCP-1 mRNA expression in TNF-alpha stimulated THP-1 monocytes (64.8% +/- 8.4% of un-treated cells). PPAR gamma activation was observed in cells treated with irbesartan (134% +/- 36% at 3 mu M to 3329% +/- 218% at 81 mu M) by a PPAR gamma reporter assay system. Conclusions: Remissions of inflammation and apoptosis as potential therapeutic effects of irbesartan on atherosclerosis were observed. The usefulness of molecular imaging using F-18-FDG and Tc-99m-annexin A5 for evaluating the therapeutic effects of irbesartan on atherosclerosis was also suggested.

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1932-6203