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

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.

The Role of Inflammation in Myocardial Infarction

“…Administration of the ARB candesartan to monocytes suppresses IL-1β/6, TNF-α, and MCP-1 levels, an effect that is mediated via an inhibition of TLR2/4 receptors [169] that are related to the inflammatory response as previously mentioned. A very recent study has reported anti-inflammatory effects of the ARB irbesartan in atheromatous plaques of apoE KO mice, via a suppression of macrophage infiltration [170]. Additionally, a meta-analysis of nine clinical trials has proven that telmisartan suppresses IL-6 and TNF-α [171], although this is not confirmed by a recent study measuring inflammatory factors in hypertensive and atherosclerotic patients [172].…”

Multimodality Molecular Imaging of Cardiovascular Disease Based on Nanoprobes

“…Several research groups have successfully imaged cell apoptosis in atherosclerotic plaques in vivo [65][66][67]. Van Tilborg et al developed and applied a small micellar fluorescent annexin A5-functionalized nanoprobe, which carried multiple Gd-labeled lipids and fluorescent lipids for both noninvasive MRI and fluorescence imaging [68].…”

A review of molecular imaging of atherosclerosis and the potential application of dendrimer in imaging of plaque

“…Thus, researchers have utilized Annexin A5 to target PS for noninvasive imaging of atherosclerotic plaques. [68][69][70] For example, 99m Tc-annexin A5 was injected to animals for noninvasive in vivo SPECT/CT imaging and the lesions were clearly visualized. The 99m Tc-annexin A5 was highly taken up in the plaques rich in macrophages.…”