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.

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.

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..

Dosage response of atherosclerotic lesions to dietary cholesterol in rabbits

2013 ◽  
Vol 22 (5) ◽  
pp. 1-7 ◽  
Author(s):  
Byungrok Min ◽  
Ki Chang Nam ◽  
Min Du ◽  
Kathleen Mullin ◽  
Dong Uk Ahn
Keyword(s):  
Dietary Cholesterol ◽  
Atherosclerotic Lesions

Abstract 329: HSF-1 Knockout Enhances Dietary Cholesterol Metabolism by Inducing CYP7A1 Gene Expression and Attenuates Atherosclerosis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Govindasamy Ilangovan ◽  
Krishnamurthy Karthikeyan
Keyword(s):  
Heart Disease ◽  
Bile Acid ◽  
Heat Shock ◽  
Cholesterol Metabolism ◽  
Dietary Cholesterol ◽  
Atherosclerotic Lesion ◽  
Heat Shock Factor 1 ◽  
Mrna Levels ◽  
Gene Promoters ◽  
Gene Expressions

Objective: Coronary heart disease and diabetes are highly prevalent among obese populations due to aberrant dietary cholesterol metabolism. Here we investigated the effect of heat shock factor-1 (HSF-1) on atherosclerosis and dietary cholesterol metabolism. Methods and Results: Atherogenic western diet-induced weight gain was reduced in HSF-1 and LDLr double knock out mice (HSF-1 -/- /LDLr -/- ), compared to LDLr -/- mice. Atherosclerotic lesion growth in aortic arch and carotid regions was retarded. Also, repression of PPAR-γ2 and AMPKα expression in adipose tissue, low hepatic steatosis, and lessened plasma adiponectins and lipoproteins were observed. Furthermore, reduced heat shock proteins and their mRNA levels in atherosclerotic lesions correlated with reduction in lesion burden. In HSF-1 -/- /LDLr -/- liver, higher cholesterol 7α hydroxylase (CYP7A1, the rate limiting enzyme in the synthesis of bile acid from cholesterol) and MDR1/p-glycoprotein (bile salt transporter across the hepatocyte canalicular membrane) gene expressions were observed, consistent with higher bile acid sequestration and larger hepatic bile ducts. HSF-1 deletion, however, upregulated both CYP7A1 enzyme and MDR1/p-glycoportein expression and activities, due to removal of its repressive binding in the CYP7A1 and MDR1 gene promoters. This increased the conversion of cholesterol into 7-α-hydroxycholesterol and bile acid, and dietary cholesterol metabolism. Conclusions: HSF-1 ablation not only eliminates heat shock response to retard atherosclerosis, but it also transcriptionally upregulates CYP7A1 and MDR1/P-gp axis to increase cholesterol metabolism. Therefore, HSF-1 is a metabolic regulator of dietary cholesterol and a major contributor to heart disease among obese population.

scholarly journals Nitric oxide function in atherosclerosis

1997 ◽  
Vol 6 (1) ◽  
pp. 3-21 ◽  
Author(s):  
K. E. Matthys ◽  
H. Bult
Keyword(s):  
Nitric Oxide ◽  
Leukocyte Adhesion ◽  
Atherosclerotic Lesion ◽  
Vascular Wall ◽  
Early Event ◽  
No Production ◽  
Oxygen Intermediates ◽  
Atherosclerotic Lesions ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Atherosclerosis is a chronic inflammatory process in the intima of conduit arteries, which disturbs the endothelium-dependent regulation of the vascular tone by the labile liposoluble radical nitric oxide (NO) formed by the constitutive endothelial nitric oxide synthase (eNOS). This defect predisposes to coronary vasospasm and cardiac ischaemia, with anginal pain as the typical clinical manifestation. It is now appreciated that endothelial dysfunction is an early event in atherogenesis and that it may also involve the microcirculation, in which atherosclerotic lesions do not develop. On the other hand, the inflammatory environment in atherosclerotic plaques may result in the expression of the inducible NO synthase (iNOS) isozyme. Whether the dysfunction in endothelial NO production is causal to, or the result of, atherosclerotic lesion formation is still highly debated. Most evidence supports the hypothesis that constitutive endothelial NO release protects against atherogenesis e.g. by preventing smooth muscle cell proliferation and leukocyte adhesion. Nitric oxide generated by the inducible isozyme may be beneficial by replacing the failing endothelial production but excessive release may damage the vascular wall cells, especially in combination with reactive oxygen intermediates.

Platelet P-selectin facilitates atherosclerotic lesion development

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2661-2666 ◽  
Author(s):  
Peter C. Burger ◽  
Denisa D. Wagner
Keyword(s):  
Atherosclerotic Lesion ◽  
Soluble Form ◽  
Wild Type ◽  
Lesion Development ◽  
Atherosclerotic Lesions ◽  
Lesion Growth ◽  
Microparticle Formation ◽  
Apoe Deficient Mouse ◽  
Atherosclerotic Lesion Development

P-selectin is an adhesion molecule expressed on activated platelets and endothelium. It is known to play an important role in atherosclerosis. P-selectin also circulates in plasma in a soluble form (sP-selectin), which induces procoagulant microparticle formation. We investigated the role of platelet versus endothelial P-selectin in generating sP-selectin and in the formation of atherosclerotic lesions in the apolipoprotein E (apoE)–deficient mouse model. For this we transplanted apoE−/−P-selectin−/− and apoE−/−P-selectin+/+ lethally irradiated mice with bone marrow of either genotype. Seven months after transplantation, we determined from the chimeric animals that the majority of circulating sP-selectin was of endothelial origin. Thus, in atherosclerosis, the procoagulant sP-selectin reflects endothelial rather than platelet activation. We found that endothelial P-selectin was crucial for the promotion of atherosclerotic lesion growth because in its absence only relatively small lesions developed. However, platelet P-selectin also contributed to the lesion development because lesions in wild-type recipients receiving transplants with wild-type platelets were 30% larger than those receiving P-selectin-deficient platelets (P < .008) and were more frequently calcified (80% versus 44%). In comparison with P-selectin wild-type animals, absence of either endothelial or platelet P-selectin inhibited migration of smooth muscle cells into the lesion. Thus, in addition to endothelium, platelets and their P-selectin also actively promote advanced atherosclerotic lesion development.

Wnt5a Promotes Lysosomal Cholesterol Egress and Protects Against Atherosclerosis

2021 ◽  
Author(s):  
Sara Awan ◽  
Magalie Lambert ◽  
Ali Imtiaz ◽  
Fabien Alpy ◽  
Catherine Tomasetto ◽  
...  
Keyword(s):  
Dietary Cholesterol ◽  
Cell Types ◽  
Cholesterol Content ◽  
Cholesterol Homeostasis ◽  
Cholesterol Trafficking ◽  
Atherosclerotic Lesions ◽  
Crucial Component ◽  
Multiple Cell ◽  
Niemann Pick

Background: Impairment of cellular cholesterol trafficking is at the heart of atherosclerotic lesions formation. This involves egress of cholesterol from the lysosomes and two lysosomal proteins, the Niemann-Pick C1 (NPC1) and NPC2 that promotes cholesterol trafficking. However, movement of cholesterol out the lysosome and how disrupted cholesterol trafficking leads to atherosclerosis is unclear. As the Wnt ligand, Wnt5a inhibits the intracellular accumulation of cholesterol in multiple cell types, we tested whether Wnt5a interacts with the lysosomal cholesterol export machinery and studied its role in atherosclerotic lesions formation. Methods: We generated mice deleted for the Wnt5a gene in vascular smooth muscle cells (VSMCs). To establish whether Wnt5a also protects against cholesterol accumulation in human VSMCs, we used a CRISPR/Cas9 guided nuclease approach to generate human VSMCs knockout for Wnt5a. Results: We show that Wnt5a is a crucial component of the lysosomal cholesterol export machinery. By increasing lysosomal acid lipase expression, decreasing metabolic signaling by the mTORC1 kinase, and through binding to NPC1 and NPC2, Wnt5a senses changes in dietary cholesterol supply and promotes lysosomal cholesterol egress to the endoplasmic reticulum (ER). Consequently, loss of Wnt5a decoupled mTORC1 from variations in lysosomal sterol levels, disrupted lysosomal function, decreased cholesterol content in the ER, and promoted atherosclerosis. Conclusions: These results reveal an unexpected function of the Wnt5a pathway as essential for maintaining cholesterol homeostasis in vivo.

Pharmacological inhibition of C-C chemokine receptor 4 aggravates atherosclerosis through prevention of regulatory T cell recruitment to the lesions

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Amin ◽  
N Sasaki ◽  
S Horibe ◽  
S Kawauchi ◽  
K Hirata ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Chemokine Receptor ◽  
Flow Cytometric Analysis ◽  
Atherosclerotic Lesion ◽  
Plaque Formation ◽  
Atherosclerotic Lesions ◽  
Sites Of Action ◽  
Chemokine Receptor 4 ◽  
Deficient Mice

Abstract Background Regulatory T cells (Tregs) are demonstrated to play a protective role in the development of atherosclerosis. However, their sites of action in atherosclerosis remain unclear. Although C-C chemokine receptor 4 (CCR4) has been shown to contribute to the accumulation of Tregs in inflamed tissues and prevention of experimental autoimmune diseases, the role of CCR4 in Treg migration to atherosclerotic lesions and suppression of plaque formation remains unknown. Methods and results We intraperitoneally injected 8-week-old apolipoprotein E–deficient mice fed a normal diet with vehicle (n=9) or a 4-μg dose of a CCR4 antagonist (n=10) 3 times weekly for 8 weeks and evaluated atherosclerotic lesions at 16 weeks old. Administration of the CCR4 antagonist significantly aggravated atherosclerotic plaque formation (aortic sinus plaque area: 2.91±0.87×104 μm2 versus 5.41±0.98×104 μm2 in control vehicle-treated and CCR4 antagonist-treated mice, respectively; P&lt;0.05), associated with increased accumulation of macrophages and CD4+T cells in the plaques. Flow cytometric analysis revealed a decrease in Foxp3+ Tregs in the para-aortic lymph nodes and thoracoabdominal aortas of CCR4 antagonist-treated mice, along with a tendency toward increase in CD44highCD62Lloweffector T cells in para-aortic lymph nodes, indicating CCR4-dependent migration of Tregs to atherosclerotic lesions and their possible atheroprotective role. We observed no changes in splenic Foxp3+ Tregs and effector T cells following CCR4 antagonist treatment. We also investigated the effect of CCR4 blockade on advanced atherosclerosis using LDL receptor–deficient mice fed a high-cholesterol diet. Although 8-week treatment with the CCR4 antagonist led to a decrease in Foxp3+ Tregs in the atherosclerotic lesions, atherosclerotic lesion formation was not significantly affected, suggesting that CCR4-dependent Treg accumulation in atherosclerotic lesions is not critical for prevention of advanced atherosclerosis. Conclusions Our findings indicate an important role for CCR4 in promotion of Treg recruitment into atherosclerotic lesions and subsequent prevention of early atherosclerosis and suggest CCR4 as a novel therapeutic target for atherosclerosis. Funding Acknowledgement Type of funding source: None

Immune-Inflammation in Atherosclerosis: A New Twist in an Old Tale

2020 ◽  
Vol 20 (4) ◽  
pp. 525-545 ◽  
Author(s):  
Atefe Ghamar Talepoor ◽  
Hamed Fouladseresht ◽  
Shahdad Khosropanah ◽  
Mehrnoosh Doroudchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Drug Targets ◽  
Inflammatory Diseases ◽  
Atherosclerotic Lesion ◽  
Preventative Measures ◽  
Atherosclerotic Lesions ◽  
Adaptive Immune Cells ◽  
One Step ◽  
Immune Inflammation

Background and Objective: Atherosclerosis, a chronic and progressive inflammatory disease, is triggered by the activation of endothelial cells followed by infiltration of innate and adaptive immune cells including monocytes and T cells in arterial walls. Major populations of T cells found in human atherosclerotic lesions are antigen-specific activated CD4+ effectors and/or memory T cells from Th1, Th17, Th2 and Treg subsets. In this review, we will discuss the significance of T cell orchestrated immune inflammation in the development and progression of atherosclerosis. Discussion: Pathogen/oxidative stress/lipid induced primary endothelial wound cannot develop to a full-blown atherosclerotic lesion in the absence of chronically induced inflammation. While the primary inflammatory response might be viewed as a lone innate response, the persistence of such a profound response over time must be (and is) associated with diverse local and systemic T cell responses. The interplay between T cells and innate cells contributes to a phenomenon called immuneinflammation and has an impact on the progression and outcome of the lesion. In recent years immuneinflammation, an old term, has had a comeback in connecting the puzzle pieces of chronic inflammatory diseases. Conclusion: Taking one-step back and looking from afar at the players of immune-inflammation may help us provide a broader perspective of these complicated interactions. This may lead to the identification of new drug targets and the development of new therapies as well as preventative measures.

scholarly journals Effect of Consumption Heated Oils with or without Dietary Cholesterol on the Development of Atherosclerosis

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1527 ◽  
Author(s):  
Che Idris ◽  
Kalyana Sundram ◽  
Ahmad Razis
Keyword(s):  
Palm Olein ◽  
Corn Oil ◽  
Rabbit Model ◽  
Dietary Cholesterol ◽  
Atherosclerotic Lesion ◽  
Fibrous Plaque ◽  
Considerable Length ◽  
Radical Processes ◽  
Heated Oils ◽  
Effect Of Feeding

Heating oils and fats for a considerable length of time results in chemical reactions, leading to the aggravation of a free radical processes, which ultimately contributes to atherosclerosis. Our study focused on elucidating the effect of feeding heated oils with or without dietary cholesterol on the development of atherosclerosis in rabbits. We heated palm olein and corn oil at 180 °C for 18 h and 9 h per day, respectively, for two consecutive days. Next, 20 male rabbits were divided into four groups and fed the following diet for 12 weeks: (i) heated palm olein (HPO); (ii) HPO with cholesterol (HPOC); (iii) heated corn oil (HCO); and (iv) HCO with cholesterol (HCOC). Plasma total cholesterol (TC) was significantly lower in the HCO group compared to the HCOC group. Atherosclerotic lesion scores for both fatty plaques and fatty streaks were significantly higher in the HCO and HCOC groups as compared to the HPO and HPOC groups. Additionally, fibrous plaque scores were also higher in the HCO and HCOC groups as compared to the HPO and HPOC groups. These results suggest that heated palm oil confers protection against the onset of atherosclerosis compared to heated polyunsaturated oils in a rabbit model.

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