Identification of a danger-associated peptide from apolipoprotein B100 (ApoBDS-1) that triggers innate proatherogenic responses

Background: Subendothelial deposited low-density lipoprotein particles are a known inflammatory factor in atherosclerosis. However, the causal components derived from low-density lipoprotein are still poorly defined. Apolipoprotein B100 (ApoB100) is the unexchangeable protein component of low-density lipoprotein, and the progression of atherosclerosis is associated with immune responses to ApoB100-derived peptides. In this study, we analyzed the proinflammatory activity of ApoB100 peptides in atherosclerosis. Methods and Results: By screening a peptide library of ApoB100, we identified a distinct native peptide referred to as ApoB100 danger-associated signal 1 (ApoBDS-1), which shows sequence-specific bioactivity in stimulation of interleukin-8, CCL2, and interleukin-6. ApoBDS-1 activates mitogen-activated protein kinase and calcium signaling, thereby effecting the expression of interleukin-8 in innate immune cells. Ex vivo stimulation of carotid plaques with ApoBDS-1 enhances interleukin-8 and prostaglandin E2 release. Furthermore, we demonstrated that ApoBDS-1–positive peptide fragments are present in atherosclerotic lesions using immunoassays and that low-molecular-weight fractions isolated from plaque show ApoBDS-1 activity inducing interleukin-8 production. Conclusions: Our data show that ApoBDS-1 is a previously unrecognized peptide with robust proinflammatory activity, contributing to the disease-promoting effects of low-density lipoprotein in the pathogenesis of atherosclerosis. (Circulation. 2011;124:2433-2443.)Swedish Heart-Lung FoundationSwedish Foundation for Strategic ResearchSwedish Research CouncilCenter of Excellence for Research on Inflammation and Cardiovascular Disease Linnaeus ProgramLeducq FoundationEuropean UnionChina Scholarship Council.Publishe

Vaccination for atherosclerosis: a novel therapeutic paradigm

Numerous studies have identified a role for the innate and adaptive immune response in atherosclerosis; both pro- and antiatherogenic roles for the immune responses have been demonstrated. Common autoantigens against which an immune response has been identified in experimental and human models of atherosclerosis include oxidized low-density lipopoteins, beta2 glycoprotein 1 and heat shock protein 60. Activation of atheroprotective adaptive immune responses have been demonstrated for oxidized low-density lipoprotein-related antigens. Conversely, atheroprotection has been demonstrated with the induction of immune tolerance through activation of mucosal immunity to heat shock protein 65/60 and beta2 glycoprotein 1. Recent identification of specific immunoreactive antigenic epitopes in the apolipoprotein B-100 component of low density lipoproetin and early experimental observations have provided proof of concept that active vaccination using specific apolipoprotein B-100-related antigens may emerge as a novel immunomodulating atheroprotective strategy

Low-Grade Inflammation, Oxidative Stress and Risk of Invasive Post-Menopausal Breast Cancer - A Nested Case-Control Study from the Malmö Diet and Cancer Cohort.

Although cancer promotes inflammation, the role of inflammation in tumor-genesis is less well established. The aim was to examine if low-grade inflammation is related to post-menopausal breast cancer risk, and if obesity modifies this association.In the Malmö Diet and Cancer cohort, a nested case-control study was defined among 8,513 women free of cancer and aged 55-73 years at baseline (1991-96); 459 were diagnosed with invasive breast cancer during follow-up (until December 31st, 2010). In laboratory analyses of blood from 446 cases, and 885 controls (matched on age and date of blood sampling) we examined systemic inflammation markers: oxidized (ox)-LDL, interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, white blood cells, lymphocytes and neutrophils. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer risk was calculated using multivariable conditional logistic regression.Inverse associations with breast cancer were seen in fully-adjusted models, for 2nd and 3rd tertiles of ox-LDL, OR (95% CI): 0.65 (0.47-0.90), 0.63 (0.45-0.89) respectively, p-trend = 0.01; and for the 3rd tertile of TNF-α, 0.65 (0.43-0.99), p-trend = 0.04. In contrast, those in the highest IL-1β category had higher risk, 1.71 (1.05-2.79), p-trend = 0.01. Obesity did not modify associations between inflammation biomarkers and breast cancer.Our study does not suggest that low-grade inflammation increase the risk of post-menopausal breast cancer

Immunization with cationized BSA inhibits progression of disease in ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis.

Immune responses against modified self-antigens generated by hypercholesterolemia play an important role in atherosclerosis identifying the immune system as a possible novel target for prevention and treatment of cardiovascular disease. It has recently been shown that these immune responses can be modulated by subcutaneous injection of adjuvant. In the present study we immunized 25-week old ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis with adjuvant and two different concentrations of the carrier molecule cationized BSA (cBSA). Plasma levels of Th2-induced apolipoprotein B (apoB)/IgG1 immune complexes were increased in the cBSA immunized groups verifying induction of immunity against a self-antigen. Mice were sacrificed at 36 weeks of age and atherosclerosis was monitored by en face Oil red O staining of the aorta. Immunization with 100μg cBSA inhibited plaque progression, whereas the lower dose (50μg) did not. In addition, the higher dose induced a more stable plaque phenotype, indicated by a higher content of collagen and less macrophages and T cells in the plaques. Moreover, there was an increased ratio of Foxp3(+)/Foxp3(-) T cells in the circulation suggesting activation of a regulatory T cell response. In conclusion, we show that immunization with cBSA induces an immune response against apoB as well as an activation of Treg cells. This was associated with development of a more stable plaque phenotype and reduced atherosclerosis progression

Correlation of inflammation markers among breast cancer controls (n = 885) in the Malmö Diet and Cancer cohort.

<p>Correlation of inflammation markers among breast cancer controls (n = 885) in the Malmö Diet and Cancer cohort.</p

Association between inflammation markers and the risk of post-menopausal breast cancer in the Malmö Diet and Cancer cohort.

<p>Association between inflammation markers and the risk of post-menopausal breast cancer in the Malmö Diet and Cancer cohort.</p

Characteristics of breast cancer controls (n = 885) across levels of several inflammation markers (ox-LDL, TNF-α, and IL-1β) in the Malmö Diet and Cancer cohort.

<p>Characteristics of breast cancer controls (n = 885) across levels of several inflammation markers (ox-LDL, TNF-α, and IL-1β) in the Malmö Diet and Cancer cohort.</p