Abstract
ObjectivesTo investigate the effects of irbesartan on inflammation and apoptosis in atherosclerotic plaques by histochemical examination and molecular imaging using 14C-FDG and 99mTc-annexin A5.BackgroundIrbesartan has a peroxisome proliferator-activated receptor gamma (PPARγ) 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 18F-FDG and 99mTc-annexin A5 is useful for evaluating inflammation and apoptosis in atherosclerotic plaques.MethodsFemale 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 14C-FDG and 99mTc-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 14C-FDG and 99mTc-annexin A5 in plaques (%ID×kg). In vitro experiments were performed to investigate the mechanism underlying the effects.ResultsHistological 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%). 14C-FDG (43.0%±18.6%) and 99mTc-annexin A5 levels (45.9%±16.8%) were also significantly reduced by irbesartan treatment. Irbesartan significantly suppressed MCP-1 mRNA expression in TNF-α stimulated THP-1 monocytes (64.8%±8.4% of un-treated cells). PPARγ activation was observed in cells treated with irbesartan (134%±36% at 3 µM to 3329%±218% at 81 µM) by a PPARγ reporter assay system.ConclusionsRemissions of inflammation and apoptosis as potential therapeutic effects of irbesartan on atherosclerosis were observed. The usefulness of molecular imaging using 18F-FDG and 99mTc-annexin A5 for evaluating the therapeutic effects of irbesartan on atherosclerosis was also suggested.
Highlights
Atherosclerosis is a chronic inflammatory disease in blood vessels that is related to the renin-angiotensin system [1]
Histological examination indicated that irbesartan treatment significantly reduced plaque size, intra-plaque lipid deposition (53.6%620.2%) and macrophage infiltration (61.9%620.8%) levels, and the number of apoptotic cells (14.5%616.6%). 14C-FDG (43.0%618.6%) and 99mTc-annexin A5 levels (45.9%616.8%) were significantly reduced by irbesartan treatment
peroxisome proliferator-activated receptor gamma (PPARc) activation was observed in cells treated with irbesartan (134%636% at 3 mM to 3329%6218% at 81 mM) by a PPARc reporter assay system
Summary
Atherosclerosis is a chronic inflammatory disease in blood vessels that is related to the renin-angiotensin system [1]. Since the endothelial dysfunction denotes the initiation of atherosclerosis, enhanced inflammation promotes the development of vulnerable plaques, and reactive oxygen species (ROS) exert harmful effects such as the induction of the apoptosis of macrophage and smooth muscle cells [4,5], the blockade of the AT1 receptor may suppress atherosclerosis progression and stabilize vulnerable plaques In agreement with this concern, several experimental studies and clinical trials demonstrated that treatment with angiotensin II AT1 receptor blockers (ARBs) can attenuate atherosclerotic plaque formation, reduce cytokine expression and inflammation levels [6], and suppress oxidative stress in the vessel wall [7]. Molecular imaging using 18F-FDG and 99mTc-annexin A5 is useful for evaluating inflammation and apoptosis in atherosclerotic plaques
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