The effects of total lymphocyte deficiency on the extent of atherosclerosis in apolipoprotein E-/- mice.

Daugherty, Alan; Puré, Ellen; Delfel-Butteiger, Dustie; Chen, Sam; Leferovich, John; Roselaar, Simon E.; Rader, Daniel J.

doi:10.1172/jci119681

Cited by 233 publications

(161 citation statements)

References 46 publications

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“…However, the present finding of an association between autoantibodies against apo B peptides and CV death are well in line with accumulating evidence suggesting that immune responses against plaque antigens play an important role in atherosclerosis and that LDL is a major target for these immune responses. 16,17,21,22 Although initial studies argued for a proatherogenic effect of adaptive immunity in atherosclerosis 23 it has now become evident that the role of the immune system in the disease process is much more complex and that both pathogenic and protective responses are involved. Suppressive regulatory T cells protect against atherosclerosis through release of anti-inflammatory cytokines and suppression of autoreactive T cells in the artery wall.…”

Section: Discussionmentioning

confidence: 99%

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

Asciutto¹,

Dias²,

Edsfeldt³

et al. 2015

Atherosclerosis

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Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy.Asciutto, Giuseppe; Dias, Nuno; Edsfeldt, Andreas; Alm, Ragnar; Nordin Fredrikson, Gunilla; Goncalves, Isabel; Nilsson, Jan Link to publication Citation for published version (APA): Asciutto, G., Dias, N., Edsfeldt, A., Alm, R., Nordin Fredrikson, G., Goncalves, I., & Nilsson, J. (2015). Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy. Atherosclerosis, 239(2), 289-294. DOI: 10.1016289-294. DOI: 10. /j.atherosclerosis.2015 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Methods: Native (nat) and malondialdehyde (MDA)-modified apoB p210 autoantibodies (IgM-p210nat, IgG-p210nat, IgM-p210MDA and IgG-p210MDA) were analyzed by ELISA from plasma samples of 351 patients at the time they underwent CEA. The incidence of postoperative CV events was assessed using national registers.Results: A total of 52 non-fatal and 15 fatal CV events were registered during the follow-up period (35.1 ± 16.7 months). Patients who suffered from a fatal CV event had significantly lower plasma levels of IgG-p210nat and IgG-p210MDA. Kaplan-Meier curves of event-free survival showed increased CV mortality in patients with levels of IgG-p210nat and IgGp210MDA below the median (Log Rank 7.813, p .005 and 9.105, p .003 respectively). The association between low levels of p210 IgG and fatal post-operative CV events remained significant when adjusting for age, sex, total cholesterol, HDL cholesterol, smoking habits and hypertension in a Cox Proportional Hazard model (hazard ratios (HR) IgG-p210nat below median: HR 6.7 (95% C.I. 1.5-30.6, p .013) and IgG-p210MDA below median: HR 7.8 (95% C.I. 1.7-35.5, p .008).Conclusions: The present findings support the notion that autoantibodies against LDL antigens are involved in the atherosclerotic disease process and suggest that CEA patients with low levels of IgG-p210nat and IgG-p210MDA have an increased risk of post-operative CV death.

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Section: Discussionmentioning

confidence: 99%

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

Asciutto¹,

Dias²,

Edsfeldt³

et al. 2015

Atherosclerosis

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“…2 Serum autoantibodies titers to modified lipoproteins were determined as described previously, with data expressed as the ratio of chromagen development for LDL compared with malondialdehydemodified LDL coated plates. 23 …”

Section: Measurement Of Serum Componentsmentioning

confidence: 99%

“…23,24 The maximum width of the abdominal aorta was measured using computerized morphometry (Image-Pro). Aneurysm incidence was quantified based on a definition of an external width of the suprarenal aorta that was increased by 50% or greater compared with aortas from saline-infused mice.…”

Section: Quantification Of Atherosclerosis and Aaamentioning

confidence: 99%

Bone Marrow Transplantation Reveals That Recipient AT1a Receptors Are Required to Initiate Angiotensin II–Induced Atherosclerosis and Aneurysms

Cassis

Rateri

Lü

et al. 2007

ATVB

149

172

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Objective-Angiotensin II (AngII) infusion into hypercholesterolemic mice accelerates atherosclerosis and promotes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define whether AngII interacts with receptors on infiltrating versus resident cells in promoting vascular pathologies. Methods and Results-Male LDL receptorϪ/Ϫ mice, that were either AT1a receptor ϩ/ϩ or Ϫ/Ϫ, were fed a fat enriched diet and infused with either saline or AngII. AngII-induced augmentation of atherosclerosis and formation of AAAs was ablated in AT1a receptorϪ/Ϫ mice. Bone marrow transplantation studies were performed to determine the role of AT1a receptors expressed on infiltrating cells. AT1a receptor ϩ/ϩ and Ϫ/Ϫ mice were irradiated and repopulated with bone marrow-derived stem cells of either genotype. These 4 groups of chimeric mice were infused with either saline or AngII. Repopulation of irradiated AT1a receptor ϩ/ϩ mice with Ϫ/Ϫ bone marrow-derived cells resulted in modest reductions in AngII-induced atherosclerosis. Unexpectedly, AT1a receptor-deficient recipient mice were dramatically protected from AngII-induced vascular pathologies, irrespective of donor genotype. Conclusion-

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“…Two of these studies used lymphocyte-deficient RAG-null mice. In one study, cholesterol-fed RAG2/apoE double knockout mice were found to develop lesions at the same rate as "normal" apoE-null mice (30). Similarly, another group found that RAG1/apoE double knockout mice developed atherosclerotic lesions at essentially the same rate as normal apoE-null mice on a high-cholesterol diet (31).…”

Section: Introductionmentioning

confidence: 95%

Lymphocytes are important in early atherosclerosis

Song¹,

Leung²,

Schindler³

2001

J. Clin. Invest.

197

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Lymphocytes represent a potentially important proinflammatory cell that localizes to atherosclerotic lesions. To determine whether they contribute to lesion development, atherosclerosis-prone (LDLR -/-) mice were crossed with lymphocyte-deficient (RAG1 -/-) mice to generate double knockout progeny. After 8 weeks on a Western-type diet (WTD), lesion development was reduced by 54% in double knockout mice, as compared with matched LDLR -/-controls. However, these significant differences in lesion area gradually subsided as the WTD was continued for 12 and 16 weeks. Consistent with this observation, histological studies determined that lesion initiation and early progression were delayed in RAG1/LDL-R double knockout mice. Differences in lesion area did not correlate with any significant alterations in plasma lipid levels. These studies suggest that lymphocytes play an important role early in atherogenesis. mice were crossed with the RAG1-null mice, and atherogenesis was evaluated. Although atherosclerotic lesions were small after 4 weeks on a Western type diet (WTD), they had grown significantly by 8 weeks. Moreover, they were 54% smaller in the RAG1/LDL-R double knockout mice, suggesting lymphocyte function is important at this point in time. Lesions continued to grow with time, but the relative difference in lesion area between LDL-R-null and RAG1/LDL-R double knockout mice became less significant. These results indicate that lymphocytes play a more important role early in the pathogenesis of atherosclerotic lesions. MethodsMice. The LDL-R-null mice (in a C57BL/6 background) and RAG1-null mice (in a C57BL/6 background) were obtained from The Jackson Laboratory (Bar Harbor, Maine, USA). Mice, maintained in a specific pathogen-free facility, were interbred and genotyped by PCR as described previously (32-34). Once sufficient numbers of single-and double knockout mice were available (i.e., about ten age-and sex-matched mice for each group), they were placed on a WTD (21% fat, 0.15% cholesterol for 4-16 weeks; Harlan Teklad Laboratory, Winfield, Iowa, USA). Hearts and fasted plasma samples were collected from sacrificed mice.Histochemistry. Hearts were perfused with PBS, embedded in OCT, and snap-frozen. Then 10-µm-thick transverse sections covering 350-400 µm of the proximal aorta were collected. For atherosclerosis quantitation, every sixth section (for a total of six sections) was stained with Oil red O after fixation in 4% paraformaldehyde. Lesion area was then determined by measuring accumulated intimal lipid by video microscopy, as described previously (35-37). To evaluate lesion cellularity, nuclei were counted in serial sections that had been stained with Oil red O. Alternating sections were stained with either hematoxylin and eosin (H&E) or Trichrome after the fixation in 4% formaldehyde (22). Collagen content was determined by measuring the accumulated collagen in serial Trichrome-stained sections, as described above.Immunohistochemistry. Cold acetone fixed frozen sections were stained with an MHC-II-specif...

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The effects of total lymphocyte deficiency on the extent of atherosclerosis in apolipoprotein E-/- mice.

Cited by 233 publications

References 46 publications

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

Bone Marrow Transplantation Reveals That Recipient AT1a Receptors Are Required to Initiate Angiotensin II–Induced Atherosclerosis and Aneurysms

Lymphocytes are important in early atherosclerosis

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