Disruption of tumor necrosis factor-α gene diminishes the development of atherosclerosis in ApoE-deficient mice

Ohta, Hiroyuki; Wada, Hisayasu; Niwa, Toshifumi; Kirii, Hirokazu; Iwamoto, Naoki; Fujii, Hidehiko; Saito, Kuniaki; Sekikawa, Kenji; Seishima, Mitsuru

doi:10.1016/j.atherosclerosis.2004.11.016

Cited by 302 publications

(218 citation statements)

References 25 publications

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“…Elevated serum levels of these cytokines are generally found in patients having a poor prognosis or more severe arterial lesions (55,56). Animal models designed to decipher the role of IL-6, TNF-a, and GM-CSF in atherosclerosis have not yet been fully conclusive because experimental settings (feeding diet, location of the lesions, and sex of the animals) largely determine the outcome of lesion evolution (57)(58)(59)(60)(61)(62)(63)(64). In this study we show that IL-6, TNF-a, and GM-CSF production is inconstant but characteristic of resident B cells, whereas the lack of expression of the other tested cytokines is a permanent feature.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

Hamze

Desmetz

Berthe

et al. 2013

The Journal of Immunology

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Animal models of atherosclerosis suggest that B cells have contradictory protective or proatherogenic effects that are also subset and context dependent. To further understand the pathophysiology of human atheroma, we characterized local Ig production and functional properties of resident B cells in human arterial lesions. Ig repertoires were analyzed by RT-PCR in carotid endarterectomy samples. Cytokine, differentiation marker and transcription factor mRNA expression was studied on arterial wall lymphocytes isolated by laser capture microdissection. Ig sequence analysis revealed that individual samples each contained a limited number of B cell clones. Functional α and γ mRNAs made up the majority of H chain mRNAs in the adventitia. Clonal evolution of Ig V regions, expression of activation-induced cytidine deaminase, clonal H chain switch, and an inverted λ/κ ratio of Ig L chain usage indicated that a local differentiation process was taking place in arterial walls. Clonotypic markers revealed different plaque and adventitia Ig repertoires and a B cell recirculation between adventitia and draining lymph nodes. Microdissected mononuclear cells had an activated phenotype expressing IL-6, GM-CSF, and TNF-α, whereas IL-2, IL-4, IL-10, M-CSF, and IFN-γ were not detected. Adventitial oligoclonal resident B cells of atherosclerotic patients are mainly mature B2 (conventional) CD20− plasmablasts lacking markers of terminal differentiation to plasma cell (CD138 and Blimp-1). They present hallmarks of Ag-driven maturation and could act on inflammation and disease progression directly or by promoting polarization of other immune cells.

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Section: Discussionmentioning

confidence: 99%

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

Hamze

Desmetz

Berthe

et al. 2013

The Journal of Immunology

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“…TNF blockade is now used widely in the treatment of chronic inflammatory autoimmune disorders. Evidence from case reports (18), animal studies (19), small clinical studies (6), epidemiology studies, and clinical trials in patients with heart failure (20) indicates that TNF blockade may exert some functional effects, although the data are somewhat contradictory. Although our results on risk factors are not all in a favorable direction, the majority of changes are in a positive direction.…”

Section: Discussionmentioning

confidence: 99%

Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: A double‐blind, placebo‐controlled study

Sattar

Crompton

Cherry

et al. 2007

Arthritis & Rheumatism

110

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Objective. To conduct a robust, double-blind, placebo-controlled study examining the effects of tumor necrosis factor (TNF) modulation on concentrations of traditional and novel cardiovascular disease risk factors in patients with an inflammatory condition.Methods. In this double-blind study, 127 patients with psoriatic arthritis (PsA) and active psoriasis were randomized to 1 of 3 treatment arms (placebo, onercept 50 mg, or onercept 100 mg for 12 weeks). Traditional and novel biochemical risk factors were evaluated at baseline and at the end of the treatment period.Results. At baseline, an elevated C-reactive protein ( Conclusion. This study is the first to demonstrate that targeting the TNF pathway can significantly decrease Lp(a) and homocysteine levels and elevate Apo A-I and SHBG concentrations. These data support an important precursor role for high-grade inflammation in modulating these putative risk parameters. However, TNF blockade-induced increases in triglyceride and Apo B levels were unexpected and suggest that it is not possible, on the basis of biochemical changes in isolation, to suggest that cardioprotection would necessarily follow; rather, direct measures of atherosclerotic progression with TNF blockade (e.g., using carotid ultrasound) would be better.

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“…The progression of atherosclerosis is affected by various adipokines, cytokines produced primarily by adipose tissue 2,3 . Most adipokines, including leptin 4 , tumor necrosis factor-a (TNF-a) 5 , interleukin (IL)-18 (ref. 6) and resistin 7 , have been shown to promote atherosclerosis.…”

mentioning

confidence: 99%

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

et al. 2014

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Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-a-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.

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Disruption of tumor necrosis factor-α gene diminishes the development of atherosclerosis in ApoE-deficient mice

Cited by 302 publications

References 25 publications

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: A double‐blind, placebo‐controlled study

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

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