Abstract 3198: RAGE-directed Imaging of Atherosclerotic Plaque in a Murine Model of Spontaneous Atherosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yared Tekabe ◽  
Qing Li ◽  
Marija Sedlar ◽  
Stan Majeweski ◽  
Ann Marie Schmidt ◽  
...  
Keyword(s):  
Gamma Camera ◽  
Atherosclerotic Lesion ◽  
Blood Pool ◽  
High Cholesterol Diet ◽  
Atherosclerotic Lesions ◽  
Rabbit Igg ◽  
Glycation End Products ◽  
The Mean ◽  
Progression Of Atherosclerosis

Introduction: The receptor for advanced glycation end products (RAGE) interacts with distinct molecules implicated in the development and progression of atherosclerosis. We assessed the hypothesis that 99m Tc-labeled anti-RAGE F(ab’)2 fragments can be used as a noninvasive tool to access atherosclerotic lesion in apolipoprotein E deficient (apoE −/− ) mice. Methods: We developed a novel antibody in rabbits against the V-type Ig extracellular domain of RAGE. Five 20 wk apoE −/− mice fed a high-cholesterol diet plus 2 C57BL/6 mice were injected with 21.6 MBq (0.5 mCi) 99m Tc-labeled anti-RAGE F(ab’)2 fragments and two 20 wk apoE −/− were injected with non-immune rabbit IgG. All mice were imaged on a high resolution parallel hole gamma camera 4 hr after injection (time based on blood pool clearance). Animals were sacrificed and the aortic tree dissected and photographed, and the root and proximal aorta sectioned for immunohistochemical staining after gamma scintillation counting. Results: All five apoE −/− mice injected with 99m Tc-labeled anti-RAGE F(ab’)2 fragments were scan positive. Both disease and antibody controls were scan negative. The mean percentage injected dose per gram (%ID/g) for scan positive was 3.35 and for scan negative <1.0. In vivo image and histology are shown below. Conclusion: RAGE imaging identifies atherosclerotic lesions with vulnerable features..

scholarly journals Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

2017 ◽  
Vol 114 (13) ◽  
pp. E2766-E2775 ◽  
Author(s):  
Yaw Asare ◽  
Miriam Ommer ◽  
Florence. A. Azombo ◽  
Setareh Alampour-Rajabi ◽  
Marieke Sternkopf ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Cop9 Signalosome ◽  
Macrophage Phenotype ◽  
Ring E3 Ligase ◽  
Atherosclerotic Lesions ◽  
Arginase 1 ◽  
Proinflammatory Gene ◽  
A Subunit

Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell-expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed “deNEDDylase”) and a subunit of the cullin-RING E3 ligase-regulating COP9 signalosome complex, attenuates proinflammatory NF-κB signaling. We previously showed that CSN5 is up-regulated in human atherosclerotic arteries. Here, we investigated the role of CSN5 in atherogenesis in vivo by using mice with myeloid-specific Csn5 deletion. Genetic deletion of Csn5 in Apoe−/− mice markedly exacerbated atherosclerotic lesion formation. This was broadly observed in aortic root, arch, and total aorta of male mice, whereas the effect was less pronounced and site-specific in females. Mechanistically, Csn5 KO potentiated NF-κB signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1α levels were reduced. Inversely, inhibition of NEDDylation by MLN4924 blocked proinflammatory gene expression and NF-κB activation while enhancing HIF-1α levels and the expression of M2 marker Arginase 1 in inflammatory-elicited macrophages. MLN4924 further attenuated the expression of chemokines and adhesion molecules in endothelial cells and reduced NF-κB activation and monocyte arrest on activated endothelium in vitro. In vivo, MLN4924 reduced LPS-induced inflammation, favored an antiinflammatory macrophage phenotype, and decreased the progression of early atherosclerotic lesions in mice. On the contrary, MLN4924 treatment increased neutrophil and monocyte counts in blood and had no net effect on the progression of more advanced lesions. Our data show that CSN5 is atheroprotective. We conclude that MLN4924 may be useful in preventing early atherogenesis, whereas selectively promoting CSN5-mediated deNEDDylation may be beneficial in all stages of atherosclerosis.

scholarly journals Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

2016 ◽  
Vol 113 (41) ◽  
pp. 11525-11530 ◽  
Author(s):  
Kuei-Chun Wang ◽  
Yi-Ting Yeh ◽  
Phu Nguyen ◽  
Elaine Limqueco ◽  
Jocelyn Lopez ◽  
...  
Keyword(s):  
Target Genes ◽  
Critical Role ◽  
Atherosclerotic Lesion ◽  
Tissue Growth ◽  
Binding Motif ◽  
Disturbed Flow ◽  
Atherosclerotic Lesions ◽  
En Face

The focal nature of atherosclerotic lesions suggests an important role of local hemodynamic environment. Recent studies have demonstrated significant roles of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in mediating mechanotransduction and vascular homeostasis. The objective of this study is to investigate the functional role of YAP/TAZ in the flow regulation of atheroprone endothelial phenotypes and the consequential development of atherosclerotic lesions. We found that exposure of cultured endothelial cells (ECs) to the atheroprone disturbed flow resulted in YAP/TAZ activation and translocation into EC nucleus to up-regulate the target genes, including cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), and ankyrin repeat domain 1 (ANKRD1). In contrast, the athero-protective laminar flow suppressed YAP/TAZ activities. En face analysis of mouse arteries demonstrated an increased nuclear localization of YAP/TAZ and elevated levels of the target genes in the endothelium in atheroprone areas compared with athero-protective areas. YAP/TAZ knockdown significantly attenuated the disturbed flow induction of EC proliferative and proinflammatory phenotypes, whereas overexpression of constitutively active YAP was sufficient to promote EC proliferation and inflammation. In addition, treatment with statin, an antiatherosclerotic drug, inhibited YAP/TAZ activities to diminish the disturbed flow-induced proliferation and inflammation. In vivo blockade of YAP/TAZ translation by morpholino oligos significantly reduced endothelial inflammation and the size of atherosclerotic lesions. Our results demonstrate a critical role of the activation of YAP/TAZ by disturbed flow in promoting atheroprone phenotypes and atherosclerotic lesion development. Therefore, inhibition of YAP/TAZ activation is a promising athero-protective therapeutic strategy.

Abstract 466: Therapeutic Immunization with an Antiglycosaminoglycan Antibody Reduces Atherosclerotic Lesion Progression in Apolipoprotein E-Deficient Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Roger Sarduy ◽  
Victor Brito ◽  
Yosdel Soto ◽  
Livan Delgado-Roche ◽  
Tania Griñán ◽  
...  
Keyword(s):  
Antibody Response ◽  
Apolipoprotein E ◽  
Chondroitin Sulfate ◽  
Atherosclerotic Lesion ◽  
Ldl Oxidation ◽  
High Cholesterol Diet ◽  
Chow Diet ◽  
Aortic Lesion

Subendothelial retention of apoB-containing lipoproteins by interaction with glycosaminoglycan-side chains of proteoglycans is considered the key initiating step of atherogenesis. Previously, we characterized the antiatherogenic properties of the chimeric mAb chP3R99, which binds sulfated GAG, inhibits LDL-chondroitin sulfate (CS) association, and abrogates LDL oxidation in vitro and in vivo. In preventive settings, rabbits and mice immunized with this mAb showed reduced atherosclerotic lesions, related with the induction of anti-chondroitin sulfate (CS) antibodies. Now we focus in define the immunization schedule which can induce in apolipoprotein E-deficient (apoE-/-) the highest anti-CS antibody response and the greater reduction of atherosclerotic lesion progression. ApoE - / - mice (6-8 wk. old) fed a chow diet received four s.c. injections of 50 or 200 μg of chP3R99 mAb. Autologous antichondroitin sulfate (CS) antibody response was evaluated in sera by ELISA. Mice who were immunized with 200 μg generated a significant higher response against CS than the ones that received 50 μg. Then, to evaluate the association of the induction of a higher anti-CS response in the atherosclerotic lesion progression, apoE-/- mice fed with a high-fat high-cholesterol diet from 4 to 18 wk. of age, received 6 doses of 50, 100 or 200 μg of the mAb starting when 5% of the aortic area was covered by lesions. Animals were sacrificed and aortas isolated to determine the presence of lesions by histologic studies. Mean aortic lesion areas of 50 and 100 μg chP3R99-treated mice were significant reduced by ~40% in comparison with mice treated with an isotype-matched control mAb. In contrast, 62% reduction in total lesion area was observed in mice treated with 200 μg of chP3R99. Again, there was an association between the level of anti-CS antibody response and the reduction of atherosclerotic lesion progression. In conclusion, this study demonstrated the dose dependence of the anti-CS antibody response and its relationship with the arresting of the atherosclerotic progression induced by chP3R99 mAb immunization. Our results also supports the potential use of this antiglycosaminoglycan antibody-based immunotherapy as a novel approach to target advanced atherosclerosis

Abstract 1143: Imaging of Vasa Vasorum in Atherosclerotic Plaque with 99m Tc-labeled single chain-VEGF

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoru Ohshima ◽  
Shinichiro Fujimoto ◽  
Sotirios Tsimikas ◽  
Frank D Kolodgie ◽  
Renu Virmani ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Ex Vivo ◽  
Imaging Modality ◽  
Atherosclerotic Lesion ◽  
Vasa Vasorum ◽  
Intraplaque Hemorrhage ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Single Chain

Introduction: Adventitial vasa vasorum proliferation and neointimal neovascularization are associated with intraplaque hemorrhage, expansion of necrotic core and hence plaque vulnerability. Increased expression of VEGF and its receptors accompany neoangiogenic process. We used 99m Tc -labeled single chain VEGF (TcV) for developing potentially noninvasive imaging modality in experimentally induced aortic atherosclerotic lesion. Methods : Noninva-sive radionuclide imaging was performed with TcV (6.85 ±0. 27 mCi) in 6 NZW rabbits receiving high cholesterol diet (0.2% cholesterol, 4% fat) for one year and compared with 3 control rabbits receiving normal rabbit chow. Four hours after intravenous administration of TcV, micro SPECT/microCT imaging was performed for in vivo localization of tracer activity. Aortas were then explanted, and gamma counted for determination of % injected dose per gram (%ID/g). The aortas were then submitted for histopathologic characterization. Results : The uptake in thoracic aorta was clearly visualized non-invasively by TcV in vivo imaging in 4 of 5 rabbits in hypercholesterolemic rabbits, but not in the control animals. The %ID/g of each parts of aorta in hypercholesterolemic rabbits (Arch : 0.036 ± 0.020 %, Thoracic : 0.026 ± 0.012 %, Abd : 0.019 ± 0.009 %) was about 2.5-fold higher than that in control group (Arch : 0.014 ± 0.004 %, Thoracic : 0.009 ± 0.003 %, Abd : 0.009 ± 0.003 %) (figure a ). Ex vivo images of each group are shown as figure b . Conclusions : This preliminary study suggests a potentially novel strategy for non-invasive imaging of neoangiogenesis in atherosclerotic plaque and may allow identification of unstable plaques.

Abstract 1079: Modulation of Atherosclerotic Plaque Characteristics by Minocycline: An Evaluation by Molecular Imaging of Matrix Metalloprotainase (MMP) Expression

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Satoru Ohshima ◽  
Shinichiro Fujimoto ◽  
Hironori Nakagami ◽  
Nezam Haider ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Molecular Imaging ◽  
Low Dose ◽  
High Cholesterol Diet ◽  
High Dose ◽  
Targeted Interventions ◽  
Mmp Inhibitor ◽  
Atherosclerotic Lesions

MMP activation in atherosclerotic lesions plays an important role in plaque progression and vulnerability, and is a potential target for plaque stabilization. We evaluated the effectiveness of minocycline (MC) in modulation of plaque characteristics using molecular imaging of MMP expression, compared with fluvastatin (FS). 38 NZW rabbits with experimental atherosclerotic lesions were subjected to in vivo micro SPECT/CT imaging for the assessment of MMP activity using 99mTc-labeled broad spectrum MMP inhibitor (MPI). Atherosclerotic lesions were produced by balloon deendotheliazation of abdominal aorta, and high cholesterol diet for 4 months. Of these, 7 received low dose MC (1.5mg/kg), 7 high dose MC (3mg/kg, N=7), 6 FS (1mg/kg), and 6 combination of low dose MC and FS (MC+FS) in the fourth month, 12 received no intervention (Rx-control). 8 unmanipulated normal chow-fed rabbits were used as disease controls (Dz-control). After in vivo imaging, aortas were explanted for %ID/g MPI uptake, histological characterization, and MMP activity assays. Parallel in vitro studies were performed for the effect of MC and FS on NF-κB, VCAM-1 and MMP-9 expression from cultured TNF-α-stimulated smooth muscle cells and macrophages. Target accumulation of MPI was best visualized in atherosclerotic aorta in Rx-control atherosclerotic rabbits. % ID/g MPI in Rx-control (.10±.04%) was significantly higher than Dz-control (.016±.004%), MC-low (.081±.02%) and high (.045±.01%) dose, FS (.056±.011%), and MC+FS (.049±.005%) rabbits, and showed a significant correlation with histologically and biochemically-verified MMP-2, -9 activity. MC-treated plaques showed marked reduction in inflammation and increase in smooth muscle content. In vitro cell culture confirmed that NF-κB and VCAM-1 expression in activated VSMC were reduced by MC, and that MMP-9 expression in activated macrophage was also inhibited by MC. The present study demonstrates that MC is equally effective as FS in modulation of plaque characteristics, and that molecular imaging can characterize various biologic processes in vivo and allows for the study of the efficacy of targeted interventions.

Negatively-charged liposome nanoparticles can prevent dyslipidemia and atherosclerosis progression in the rabbit model

2021 ◽  
Vol 19 ◽  
Author(s):  
Amir Abbas Momtazi-Borojeni ◽  
Elham Abdollahi ◽  
Mahmoud R. Jaafari ◽  
Maciej Banach ◽  
Gerald F. Watts ◽  
...  
Keyword(s):  
Rabbit Model ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Saline Control ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Mean Values ◽  
Atherosclerotic Lesions ◽  
The Impact ◽  
Progression Of Atherosclerosis

Background and Aim: Negatively charged nanoliposomes have a strong attraction towards plasma lipoprotein particles and can thereby regulate lipid metabolism. Here, the impact of such nanoliposomes on dyslipidaemia and progression of atherosclerosis was investigated in a rabbit model. Methods: Two sets of negatively-charged nanoliposome formulations including [hydrogenated soy phosphatidylcholine (HSPC)/1,2-distearoyl-sn-glycero-3- phosphoglycerol (DSPG)] and [1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)/1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPG)/Cholesterol] were evaluated. Rabbits fed a high-cholesterol diet were randomly divided into 3 groups (n=5/group) intravenously administrated with HSPC/DSPG formulation (DSPG group; 100 mmol/kg), DMPC/DMPG formulation (DMPG group; 100 mmol/kg), or the normal saline (control group; 0.9% NaCl) over a 4-week period. The atherosclerotic lesions of the aortic arch wall were studied using haematoxylin and eosin staining. Results: Both DSPG and DMPG nanoliposome formulations showed a nano-sized range in diameter with a negatively-charged surface and a polydispersity index of <0.1. After 4 weeks administration, the nanoliposome formulations decreased triglycerides (-62±3% [DSPG group] and -58±2% [DMPG group]), total cholesterol (-58±9% [DSPG group] and -37±5% [DMPG group]), and low-density lipoprotein cholesterol (-64±6% [DSPG group] and -53±10% [DMPG group]) levels, and increased high-density lipoprotein cholesterol (+67±28% [DSPG group] and +35±19% [DMPG group]) levels compared with the controls. The nanoliposomes showed a significant decrease in the severity of atherosclerotic lesions: mean values of the intima to media ratio in DMPG (0.96±0.1 fold) and DSPG (0.54±0.02 fold) groups were found to be significantly lower than that in the control (1.2±0.2 fold) group (p<0.05). Conclusion: Anionic nanoliposomes containing [HSPC/DSPG] and [DMPC/DMPG] correct dyslipidaemia and inhibit the progression of atherosclerosis.

scholarly journals Atherosclerotic lesion-specific copper delivery suppresses atherosclerosis in high-cholesterol-fed rabbits

2021 ◽  
pp. 153537022110465
Author(s):  
Na Wang ◽  
Xinwen Xu ◽  
Hualin Li ◽  
Qipu Feng ◽  
Hongge Wang ◽  
...  
Keyword(s):  
Dietary Cholesterol ◽  
Atherosclerotic Lesion ◽  
Atherosclerotic Lesions ◽  
Copper Supplementation ◽  
New Zealand White Rabbits ◽  
Endothelial Cell Death ◽  
The Stability ◽  
Copper Delivery ◽  
Ultrasound Sonication ◽  
Progression Of Atherosclerosis

Dietary cholesterol supplements cause hypercholesterolemia and atherosclerosis along with a reduction of copper concentrations in the atherosclerotic wall in animal models. This study was to determine if target-specific copper delivery to the copper-deficient atherosclerotic wall can block the pathogenesis of atherosclerosis. Male New Zealand white rabbits, 10-weeks-old and averaged 2.0 kg, were fed a diet containing 1% (w/w) cholesterol or the same diet without cholesterol as control. Twelve weeks after the feeding, the animals were injected with copper-albumin microbubbles and subjected to ultrasound sonication specifically directed at the atherosclerotic lesions (Cu-MB-US) for target-specific copper delivery, twice a week for four weeks. This regiment was repeated 3 times with a gap of two weeks in between. Two weeks after the last treatment, the animals were harvested for analyses of serum and aortic pathological changes. Compared to controls, rabbits fed cholesterol-rich diet developed atherosclerotic lesion with a reduction in copper concentrations in the lesion tissue. Cu-MB-US treatment significantly increased copper concentrations in the lesion, and reduced the size of the lesion. Furthermore, copper repletion reduced the number of apoptotic cells as well as the content of cholesterol and phospholipids in the atherosclerotic lesion without a disturbance of the stability of the lesion. The results thus demonstrate that target-specific copper supplementation suppresses the progression of atherosclerosis at least in part through preventing endothelial cell death, thus reducing lipid infiltration in the atherosclerotic lesion.

Uterine expression of implantation serine proteinase 2 during the implantation period and in vivo inhibitory effect of its antibody on embryo implantation in mice

2004 ◽  
Vol 16 (3) ◽  
pp. 379 ◽  
Author(s):  
Z. P. Huang ◽  
H. Yu ◽  
Z. M. Yang ◽  
W. X. Shen ◽  
J. Wang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Early Pregnancy ◽  
Embryo Implantation ◽  
Serine Proteinase ◽  
Inhibitory Effect ◽  
Uterine Lumen ◽  
Rabbit Igg ◽  
The Mean ◽  
Implantation Period

The aim of the present study was to examine the uterine expression pattern of implantation serine proteinase 2 (ISP2) protein during early pregnancy in mice and the effects of anti-ISP2 antibody on embryo implantation. Expression of ISP2 protein was found to be specifically up-regulated in mouse uterine endometrial glands following the initiation of embryo implantation. Similarly, ISP2 protein expression was observed during pseudopregnancy, indicating that its expression is not embryo dependent. In other experiments, rabbit anti-ISP2 IgG was infused into the mouse uterine lumen on Day 3 or 4 of pregnancy to examine its effects on embryo implantation, whereas vehicle (saline) or unspecific rabbit IgG served as controls. The mean number of implanted embryos from anti-ISP2-IgG-treated mice was significantly lower than that from control mice. These results suggest that ISP2 may play an important role during embryo implantation.

Abstract 409: Is Accelerated Atherosclerosis a Microvascular Complication of Diabetes?

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Heidi K Stoute ◽  
Daniel Venegas-Pino ◽  
Kaley J Veerman ◽  
Geoff H Werstuck
Keyword(s):  
Atherosclerotic Lesion ◽  
Vasa Vasorum ◽  
Lesion Volume ◽  
Lesion Area ◽  
Accelerated Atherosclerosis ◽  
Microvascular Changes ◽  
Atherosclerotic Lesions ◽  
Increased Risk ◽  
Deficient Mice ◽  
Progression Of Atherosclerosis

Introduction: The complications of diabetes have traditionally been categorized as micro- or macrovasculature in nature. Individuals with diabetes are at an increased risk of macrovascular complications, including cardiovascular disease and stroke, and also suffer from microvascular disorders including retinopathy, nephropathy and neuropathy. There is increasing evidence these micro- and macrovascular conditions may be linked. Our objective is to determine if direct effects of hyperglycemia on a specific microvascular bed, the vasa vasorum, promotes diabetes-associated accelerated atherosclerosis. Methods and Results: The effects of hyperglycemia on retinal and vasa vasorum neovascularization and aortic atherogenesis were examined in streptozotocin-injected apolipoprotein-E deficient (ApoE-/-) mice and normoglycemic ApoE-/- controls. Microvessel densities of the retina and vasa vasorum were quantified at 5, 10, 15 and 20 weeks of age. Atherosclerotic lesion volume in the ascending aorta was determined at the same time points. The expression levels of pro-angiogenic factors, VEGF and VEFGR2, were also determined. Data from normoglycemic ApoE-deficient mice indicate that there is an expansion in vasa vasorum density as the atherosclerotic lesion area increases. In contrast, hyperglycemic ApoE-/- mice have significantly larger atherosclerotic lesions (2 fold, P<0..05) but have no detectible neovascularization of the vasa vasorum A deficiency in VEGF expression in the artery walls of the hyperglycemic mice may explain lack of neovascularization. Conclusions: These findings indicate that the microvessel structure of the vasa vasorum is altered by hyperglycaemia. The development and progression of atherosclerosis in hyperglycemic ApoE-deficient mice directly correlates with, and may be influenced by, microvascular changes.

scholarly journals Chlamydia pneumoniae and Hyperlipidemia Are Co-Risk Factors for Atherosclerosis: Infection Prior to Induction of Hyperlipidemia Does Not Accelerate Development of Atherosclerotic Lesions in C57BL/6J Mice

2002 ◽  
Vol 70 (9) ◽  
pp. 5332-5334 ◽  
Author(s):  
Erwin Blessing ◽  
Lee Ann Campbell ◽  
Michael E. Rosenfeld ◽  
Cho-chou Kuo
Keyword(s):  
Chlamydia Pneumoniae ◽  
Atherosclerotic Lesion ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat ◽  
Lesion Development ◽  
Atherosclerotic Lesions ◽  
Accelerate Development ◽  
Atherosclerotic Lesion Development

ABSTRACT Chlamydia pneumoniae has been shown to accelerate atherosclerotic lesion development in hyperlipidemic animals. This study showed that C. pneumoniae did not accelerate lesion development in mice if a high-fat/high-cholesterol diet was started after infection, indicating that C. pneumoniae is a co-risk factor with hyperlipidemia for cardiovascular disease.

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