Oxidized LDL induces alternative macrophage phenotype through activation of CD36 and PAFR

OxLDL is recognized by macrophage scavenger receptors, including CD36; we have recently found that Platelet-Activating Factor Receptor (PAFR) is also involved. Since PAFR in macrophages is associated with suppressor function, we examined the effect of oxLDL on macrophage phenotype. It was found that the presence of oxLDL during macrophage differentiation induced high mRNA levels to IL-10, mannose receptor, PPARγ and arginase-1 and low levels of IL-12 and iNOS. When human THP-1 macrophages were pre-treated with oxLDL then stimulated with LPS, the production of IL-10 and TGF-β significantly increased, whereas that of IL-6 and IL-8 decreased. In murine TG-elicited macrophages, this protocol significantly reduced NO, iNOS and COX2 expression. Thus, oxLDL induced macrophage differentiation and activation towards the alternatively activated M2-phenotype. In murine macrophages, oxLDL induced TGF-β, arginase-1 and IL-10 mRNA expression, which were significantly reduced by pre-treatment with PAFR antagonists (WEB and CV) or with antibodies to CD36. The mRNA expression of IL-12, RANTES and CXCL2 were not affected. We showed that this profile of macrophage activation is dependent on the engagement of both CD36 and PAFR. We conclude that oxLDL induces alternative macrophage activation by mechanisms involving CD36 and PAFR

Boosting Adaptive Immunity: A New Role for PAFR Antagonists.

We have previously shown that the Platelet-Activating Factor Receptor (PAFR) engagement in murine macrophages and dendritic cells (DCs) promotes a tolerogenic phenotype reversed by PAFR-antagonists treatment in vitro. Here, we investigated whether a PAFR antagonist would modulate the immune response in vivo. Mice were subcutaneously injected with OVA or OVA with PAFR-antagonist WEB2170 on days 0 and 7. On day 14, OVA-specific IgG2a and IgG1 were measured in the serum. The presence of WEB2170 during immunization significantly increased IgG2a without affecting IgG1 levels. When WEB2170 was added to OVA in complete Freund's adjuvant, enhanced IgG2a but not IgG1 production was also observed, and CD4+ FoxP3+ T cell frequency in the spleen was reduced compared to mice immunized without the antagonist. Similar results were observed in PAFR-deficient mice, along with increased Tbet mRNA expression in the spleen. Additionally, bone marrow-derived DCs loaded with OVA were transferred into naïve mice and their splenocytes were co-cultured with fresh OVA-loaded DCs. CD4(+) T cell proliferation was higher in the group transferred with DCs treated with the PAFR-antagonist. We propose that the activation of PAFR by ligands present in the site of immunization is able to fine-tune the adaptive immune response

Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis

Background and Purpose: Inflammation plays a key role in atherosclerosis. A protective role of angiotensin-(1-7) in vascular pathologies opened a possibility for therapeutic use of small molecule non-peptide Ang-(1-7) mimetics, such as AVE0991. The mechanisms of these vaso-protective effects of a Mas receptor agonist, AVE0991, remain unclear. Experimental approach: We investigated the effects of AVE0991 on the spontaneous atherosclerosis in ApoE-/- mice, in the context of vascular inflammation and plaque stability. Key Results: AVE0991 has significant anti-atherosclerotic properties in ApoE-/- mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using descending aorta of chow fed ApoE-/- mice, before significant atherosclerotic plaque develops, we gained insight to early events in atherosclerosis. Interestingly, perivascular adipose tissue (pVAT) and adventitial infiltration with macrophages and T cells precedes atherosclerotic plaque or the impairment of endothelium-dependent NO bioavailability as a measure of endothelial function. AVE0991 inhibited perivascular inflammation, through the reduction of chemokine expression in pVAT, as well as through direct actions on monocytes/macrophages inhibiting their activation, characterized by IL-1β, TNF-α, MCP-1 and CXCL10 and differentiation to M1 phenotype. Pre-treatment with AVE0991 inhibited migration of THP-1 monocytes towards supernatants of activated adipocytes (SW872). Mas receptors were expressed in pVAT and in THP-1 cells in vitro and anti-inflammatory effects of AVE0991 were partially Mas dependent. Conclusions & implications: Selective Mas receptor agonist AVE0991 possesses anti-atherosclerotic and anti-inflammatory properties, affecting monocyte/macrophage differentiation and recruitment to perivascular space at early stages of atherosclerosis in ApoE-/- mice

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

Light scattering from disordered overlayers of metallic nanoparticles

We develop a theory for light scattering from a disordered layer of metal nanoparticles resting on a sample. Averaging over different disorder realizations is done by a coherent potential approximation. The calculational scheme takes into account effects of retardation, multipole excitations, and interactions with the sample. We apply the theory to a system similar to the one studied experimentally by Stuart and Hall [Phys. Rev. Lett. {\bf 80}, 5663 (1998)] who used a layered Si/SiO$_2$/Si sample. The calculated results agree rather well with the experimental ones. In particular we find conspicuous maxima in the scattering intensity at long wavelengths (much longer than those corresponding to plasmon resonances in the particles). We show that these maxima have their origin in interference phenomena in the layered sample.Comment: 19 pages, 12 figure

Incidence, Outcomes, and Predictors of Ventricular Thrombus after Reperfused ST-Segment-Elevation Myocardial Infarction by Using Sequential Cardiac MR Imaging

[EN] Purpose: To characterize the incidence, outcomes, and predictors of left ventricular (LV) thrombus by using sequential cardiac magnetic resonance (MR) imaging after ST-segment-elevation myocardial infarction (STEMI). Materials and Methods: Written informed consent was obtained from all patients, and the study protocol was approved by the committee on human research. In a cohort of 772 patients with STEMI, 392 (mean age, 58 years; range, 24-89 years) were retrospectively selected who were studied with cardiac MR imaging at 1 week and 6 months. Cardiac MR imaging guided the initiation and withdrawal of anticoagulants. Patients with LV thrombus at 6 months were restudied at 1 year. For predicting the occurrence of LV thrombus, a multiple regression model was applied. Results: LV thrombus was detected in 27 of 392 patients (7%): 18 (5%) at 1 week and nine (2%) at 6 months. LV thrombus resolved in 22 of 25 patients (88%) restudied within the first year. During a mean follow-up of 181 weeks 6 168, patients with LV thrombus displayed a very low rate of stroke (0%), peripheral embolism (0%), and severe hemorrhage (n = 1, 3.7%). LV ejection fraction (LVEF) less than 50% (P < .001) and anterior infarction (P = .008) independently helped predict LV thrombus. The incidence of LV thrombus was as follows: (a) nonanterior infarction, LVEF 50% or greater (one of 135, 1%); (b) nonanterior infarction, LVEF less than 50% (one of 50, 2%); (c) anterior infarction, LVEF 50% or greater (two of 92, 2%); and (d) anterior infarction, LVEF less than 50% (23 of 115, 20%) (P < .001 for the trend). Conclusion: Cardiac MR imaging contributes information for the diagnosis and therapy of LV thrombus after STEMI. Patients with simultaneous anterior infarction and LVEF less than 50% are at highest risk. (C) RSNA, 2017Study supported by Instituto de Salud Carlos III and FEDER (CB16/11/00486, PI14/00271, PIE15/00013) and Generalitat Valenciana (PROMETEO/2013/007).Cambronero-Cortinas, E.; Bonanad, C.; Monmeneu, J.; López-Lereu, M.; Gavara-Doñate, J.; De Dios, E.; Rios, C.... (2017). Incidence, Outcomes, and Predictors of Ventricular Thrombus after Reperfused ST-Segment-Elevation Myocardial Infarction by Using Sequential Cardiac MR Imaging. Radiology. 284(2):372-380. https://doi.org/10.1148/radiol.2017161898S372380284

Magnetic resonance microscopy and correlative histopathology of the infarcted heart

Altres ajuts:The present study was supported by the EU Joint Programming Initiative 'A Healthy Diet for a Healthy Life' (JPI HDHL INTIMIC-085), Generalitat Valenciana (GV/2018/116), INCLIVA and Universitat de Valencia (program VLC-BIOCLINIC 20-nanomIRM-2016A).Delayed enhancement cardiovascular magnetic resonance (MR) is the gold-standard for non-invasive assessment after myocardial infarction (MI). MR microscopy (MRM) provides a level of detail comparable to the macro objective of light microscopy. We used MRM and correlative histopathology to identify infarct and remote tissue in contrast agent-free multi-sequence MRM in swine MI hearts. One control group (n = 3 swine) and two experimental MI groups were formed: 90 min of ischemia followed by 1 week (acute MI = 6 swine) or 1 month (chronic MI = 5 swine) reperfusion. Representative samples of each heart were analysed by contrast agent-free multi-sequence (T1-weighting, T2-weighting, T2*-weighting, T2-mapping, and T2*-mapping). MRM was performed in a 14-Tesla vertical axis imager (Bruker-AVANCE 600 system). Images from MRM and the corresponding histopathological stained samples revealed differences in signal intensities between infarct and remote areas in both MI groups (p-value < 0.001). The multivariable models allowed us to precisely classify regions of interest (acute MI: specificity 92% and sensitivity 80%; chronic MI: specificity 100% and sensitivity 98%). Probabilistic maps based on MRM images clearly delineated the infarcted regions. As a proof of concept, these results illustrate the potential of MRM with correlative histopathology as a platform for exploring novel contrast agent-free MR biomarkers after MI

Common variants of the liver fatty acid binding protein gene influence the risk of type 2 diabetes and insulin resistance in Spanish population

Summary: The main objective was to evaluate the association between SNPs and haplotypes of the FABP1-4 genes and type 2 diabetes, as well as its interaction with fat intake, in one general Spanish population. The association was replicated in a second population in which HOMA index was also evaluated. Methods: 1217 unrelated individuals were selected from a population-based study [Hortega study: 605 women; mean age 54 y; 7.8% with type 2 diabetes]. The replication population included 805 subjects from Segovia, a neighboring region of Spain (446 females; mean age 52 y; 10.3% with type 2 diabetes). DM2 mellitus was defined in a similar way in both studies. Fifteen SNPs previously associated with metabolic traits or with potential influence in the gene expression within the FABP1- 4 genes were genotyped with SNPlex and tested. Age, sex and BMI were used as covariates in the logistic regression model. Results:One polymorphism (rs2197076) and two haplotypes of the FABP-1 showed a strong association with the risk of DM2 in the original population. This association was further confirmed in the second population as well as in the pooled sample. None of the other analyzed variants in FABP2, FABP3 and FABP4 genes were associated. There was not a formal interaction between rs2197076 and fat intake. A significant association between the rs2197076 and the haplotypes of the FABP1 and HOMA-IR was also present in the replication population. Conclusions: The study supports the role of common variants of the FABP-1 gene in the development of type 2 diabetes in Caucasians