Novel Reversible Model of Atherosclerosis and Regression Using Oligonucleotide Regulation of the LDL Receptor

Basu, Debarati; Hu, Yixin; Huggins, Lesley-Ann; Mullick, Adam E.; Graham, Mark; Wietecha, Tomasz; Barnhart, Shelley; Mogul, Allison S.; Pfeiffer, Kai; Zirlik, Andreas; Fisher, Edward A.; Bornfeldt, Karin E.; Willecke, Florian; Goldberg, Ira J.

doi:10.1161/circresaha.117.311361

Cited by 54 publications

(46 citation statements)

References 44 publications

(39 reference statements)

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“…In white adipose tissue, there were no consistent effects on browning genes in visceral or subcutaneous depots and no enhancement of browning genes in BAT, suggesting a nonbrowning mechanism of enhanced energy expenditure and reduced adiposity. Although atherosclerotic lesion size was unaffected, the improvements in metabolic parameters with flavonoid intervention correlated with a reduction in circulating monocytes and reduced macrophage content in established atherosclerotic lesions, characteristics consistent with atherosclerosis regression (22).…”

Section: Discussionmentioning

confidence: 72%

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Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr−/− mice

Burke

Sutherland

Telford

et al. 2018

Journal of Lipid Research

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Obesity and its associated metabolic dysfunction and cardiovascular disease risk represent a leading cause of adult morbidity worldwide. Currently available pharmacological therapies for obesity have had limited success in reversing existing obesity and metabolic dysregulation. Previous prevention studies demonstrated that the citrus flavonoids, naringenin and nobiletin, protect against obesity and metabolic dysfunction in mice fed a high-fat cholesterol-containing (HFHC) diet. However, their effects in an intervention model are unknown. In this report, we show that, in mice with diet-induced obesity, citrus flavonoid supplementation to a HFHC diet reversed existing obesity and adipocyte size and number through enhanced energy expenditure and increased hepatic fatty acid oxidation. Caloric intake was unaffected and no evidence of white adipose tissue browning was observed. Reversal of adiposity was accompanied by improvements in hyperlipidemia, insulin sensitivity, hepatic steatosis, and a modest reduction in blood monocytes. Together, this resulted in atherosclerotic lesions that were unchanged in size, but characterized by reduced macrophage content, consistent with a more stable plaque phenotype. These studies further suggest potential therapeutic utility of citrus flavonoids, especially in the context of existing obesity, metabolic dysfunction, and cardiovascular disease.

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Section: Discussionmentioning

confidence: 72%

“…Correction of metabolic parameters was accompanied by a reduction in circulating blood monocytes. Collectively, these metabolic improvements did not resolve the size of aortic sinus atherosclerotic lesions, but plaques in flavonoid-treated mice were characterized by reduced macrophage and cholesterol content, consistent with lesion regression (21,22).…”

mentioning

confidence: 99%

Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr−/− mice

Burke

Sutherland

Telford

et al. 2018

Journal of Lipid Research

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“…Mice were maintained in a temperature-controlled (25 °C) facility with a 12-h light/dark cycle. Mice were placed on a diet containing 60% kcal from fat and 0.3% from cholesterol (Research Diets) and injected weekly with 5 mg/kg low-density lipoprotein receptor antisense oligonucleotide for 24 weeks, as described previously [22]. The antisense oligonucleotide was generously provided by Ionis Pharmaceuticals.…”

Section: Methodsmentioning

confidence: 99%

Single-Cell RNA Sequencing of Visceral Adipose Tissue Leukocytes Reveals that Caloric Restriction Following Obesity Promotes the Accumulation of a Distinct Macrophage Population with Features of Phagocytic Cells

et al. 2019

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Obesity can lead to type 2 diabetes and is an epidemic. A major contributor to its adverse effects is inflammation of the visceral adipose tissue (VAT). Lifelong caloric restriction (CR), in contrast, results in extended lifespan, enhanced glucose tolerance/insulin sensitivity, and other favorable phenotypes. The effects of CR following obesity are incompletely established, but studies show multiple benefits. Many leukocyte types, macrophages predominantly, reside in VAT in homeostatic and pathological states. CR following obesity transiently increases VAT macrophage content prior to resolution of inflammation and obesity, suggesting that macrophage content and phenotype play critical roles. Here, we examined the heterogeneity of VAT leukocytes and the effects of obesity and CR. In general, our single-cell RNA-sequencing data demonstrate that macrophages are the most abundant and diverse subpopulation of leukocytes in VAT. Obesity induced significant transcriptional changes in all 15 leukocyte subpopulations, with many genes showing coordinated changes in expression across the leukocyte subpopulations. Additionally, obese VAT displayed expansion of one major macrophage subpopulation, which, in silico, was enriched in lipid binding and metabolic processes. This subpopulation returned from dominance in obesity to lean proportions after only 2 weeks of CR, although the pattern of gene expression overall remained similar. Surprisingly, CR VAT is dominated by a different macrophage subpopulation, which is absent in lean conditions. This subpopulation is enriched in genes related to phagocytosis and we postulate that its function includes clearance of dead cells, as well as excess lipids,

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“…Stability of the plaque also determines the fate of the fibroatheroma. Unstable fibroatheroma leads to thrombotic plaque formation, whereas stable fibroatheroma accumulates calcium, becomes stiff, and eventually leads to occlusion [44,45]. Unstable or vulnerable plaques may lead to a catastrophic transition into atherosclerotic lesion-frank plaque rupture, with luminal release of the highly thrombogenic contents [46,47].…”

Section: Endothelial Dysfunction In Atherosclerosismentioning

confidence: 99%

Endothelial Dysfunction in Cardiovascular Diseases

Biswas¹,

Khan²

2020

Basic and Clinical Understanding of Microcirculation

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Endothelium is the inner most cell layer of blood vessels. Endothelial cells make special barrier that separate blood from extravascular tissues. Intact endothelium regulates vascular tone and permeability and maintains non-inflammatory, anti-thrombotic surface. Through its ability to express pro-coagulants, anticoagulants, vasoconstrictors, vasodilators, cell adhesion molecules, and cytokines, the endothelium has emerged as one of the pivotal regulators of vascular homeostasis. Under physiological conditions, endothelial cell sustains a vasodilatory, anticoagulant, and fibrinolytic state in which coagulation, platelet adhesion, as well as leukocyte activation and inflammation are suppressed. In contrast, during endothelial disturbances, a prothrombotic and pro-inflammatory state of vasoconstriction gets support from the endothelial surface. Release of platelet-activating factor (PAF) and endothelin-1 promotes vasoconstriction, whereas production of von Willebrand factor (vWF), tissue factor (TF), and plasminogen activator inhibitor (PAI)-1 shifts the haemostatic balance towards a procoagulant state. Several factors like infection, hyperglycaemia, hyperlipidaemia, malignancy, oxidative stress, and aging can interfere in endothelial function. It is believed that most of the cardiovascular diseases originate from endothelial dysfunction. Endothelial dysfunction has been shown to be involved in atherosclerosis, thrombosis, hypertension, diabetes, and other cardiovascular diseases. In this review we will specifically highlight the role of endothelial dysfunction in development of cardiovascular diseases.

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Novel Reversible Model of Atherosclerosis and Regression Using Oligonucleotide Regulation of the LDL Receptor

Cited by 54 publications

References 44 publications

Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr−/− mice

Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr−/− mice

Single-Cell RNA Sequencing of Visceral Adipose Tissue Leukocytes Reveals that Caloric Restriction Following Obesity Promotes the Accumulation of a Distinct Macrophage Population with Features of Phagocytic Cells

Endothelial Dysfunction in Cardiovascular Diseases

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