Search

Background and aims: Obese individuals have a higher risk of developing atherosclerosis, possibly driven by adipose tissue (AT) inflammation. We recently showed that AT macrophages (ATMs), which accumulate in the expanding obese AT, produce mediators causing immune cell recruitment from the bone marrow. In the current study, we evaluated whether ATMs are directly involved in atherosclerotic plaque development.Methods: Lean ldlr(-/-) acceptor mice received visceral AT (vAT) from lean, obese, or ATM-depleted obese ldlr(-/-) mice. Acceptor mice were fed high cholesterol diet (HCD) for 4 weeks before and 8 weeks after AT transplantation to induce atherosclerosis. Atherosclerotic plaque development was studied 8 weeks after transplantation.Results: Transplanting donor vAT from obese mice increased circulating triglycerides and B-cells, but decreased Ly6c(-) monocytes. Plasma cholesterol, Ly6c(+) monocytes, T-cells, NK-cells and eosinophils were unaffected. Depleting ATMs from obese AT using clodronate liposomes prior to vAT transplantation prevented the increase in triglycerides and B-cells and decrease in Ly6c(-) monocytes, but did increase eosinophils. Circulating Cxcl1 was reduced by obese AT transplantation and Ifn-gamma tended to be increased while Tnf and Il-1 beta were unaffected. ATM-depleted obese AT transplantation also reduced Cxcl1, but increased circulating Tnf levels. However, obese AT transplantation with or without depletion of ATMs did not influence atherosclerotic plaque size, phenotype, or stability.Conclusions: ATMs from obese vAT do not affect atherosclerotic plaque development or phenotype.

Background and aims: Arterial remodelling aims at normalising circumferential wall stress (CWS). Greater CWS in the carotid artery has previously been associated with the prevalence and severity of cerebral small vessel disease, a major cause of ageing-related cognitive decline. Here we test the hypothesis that greater carotid CWS is associated with poorer cognitive performance.Methods: We studied 722 individuals (60 +/- 8 years, 55% men, 42.5% highly educated, blood pressure 137 +/- 19/77 +/- 11 mmHg, n = 197 with type 2 diabetes) who completed a neuropsychological assessment and underwent vascular ultrasound to measure the intima-media thickness (IMT) and interadventitial diameter (IAD) of the left common carotid artery at a plaque-free site. From IMT and IAD, lumen diameter (LD) was calculated. These structural measures were then combined with local carotid pulse pressure and brachial mean arterial pressure to obtain a measure of pulsatile (CWSpulsatile) and average (CWSmean) mechanical load on the vessel wall. Cognitive domains assessed were memory, executive function and attention, and processing speed.Results: After adjustment for age, sex, and education, regression analyses showed that neither CWSpulsatile nor CWSmean were associated with measures of cognitive performance (p-values >= 0.31). This null association did not differ by age or educational level, and was observed in both individuals with and without carotid plaque, diabetes and/or hypertension. In addition, none of the individual measures of carotid structure (i.e. IMT, IAD, and LD) was related to cognitive performance.Conclusions: The present cross-sectional study shows that carotid CWS is not associated with cognitive performance, at least not among relatively highly educated individuals in late middle age with adequately controlled cardiovascular risk factors. (c) 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Aim The aim of the present study were to elucidate the role of NAMPT in atherosclerosis, by examine NAMPT expression in peripheral blood mononuclear cells (PBMC) in patients with coronary artery disease (CAD) and healthy controls and by examining the regulation and effect of NAMPT on macrophage polarization, hypothesizing that it could influence the polarization to inflammatory and resolving macrophages. Method and Results We analyzed RNA levels of NAMPT in PBMC from CAD and healthy controls and found NAMPT to be increased in PBMC from patients with acute coronary syndrome (n = 39) compared to healthy controls (n = 20) and patients with stable CAD (n = 22). Within the PBMC NAMPT was correlated to several inflammatory cytokines and the antioxidant enzyme superoxide dismutase 2. In vitro cell experiments revealed that NAMPT is increased both intracellular and extracellular in inflammatory M1 macrophages compared to in anti-inflammatory M2 macrophages. In addition, inhibiting NAMPT enzymatic activity inhibited M1 polarization in macrophages. Conclusion Based on our in vivo and in vitro findings we suggest that NAMPT could contribute to systemic and plaque inflammation in atherosclerotic disorders at least partly through effect on macrophages.

Objective Recent data suggest the involvement of dectin-1 in atherosclerosis through regulation of local reactive oxygen species production. The aim of the current study was to assess the effect of dectin-1 deficiency on atherosclerotic plaque development. Methods Using immunohistochemistry dectin-1 expression was observed on foamy macrophages in atherosclerotic lesions in mice. Following lethal irradiation LDLR −/− mice were reconstituted with bone marrow from either wild type or dectin-1 −/− mice. After recovery, mice were fed a high fat diet for 9 weeks and atherosclerotic lesions were analyzed. Results and conclusion Overall, we found no significant differences in plaque size or severity between the groups. Also no differences were observed in granulocyte or macrophage composition of the plaques or in the ability to produce reactive oxygen species by macrophages from both groups. Dectin-1 is dispensable for the development of atherosclerotic lesions in mice.

Objective Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis. Methods Hypercholesterolemic (low-density lipoprotein receptor−/− apolipoprotein B100/100) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4–8.To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics. Results Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (−72%, p, Highlights • Antibody-mediated Ang-2 blockage delays fatty streak formation in mice. • Ang-2 blockage lowers plasma triglyceride levels. • Ang-2 blockage has no negative effects on preexisting atherosclerosis.

Background Junctional adhesion molecule (JAM-) A is a transmembrane protein expressed in many cell types and maintains junctional integrity in endothelial cells. Upon inflammatory stimulation, JAM-A relocates to the apical surface and might thereby facilitate the recruitment of leukocytes. Objective Although inflammatory JAM-A redistribution is an established process, further effort is required to understand its exact role in the transmigration of mononuclear cells, particularly under atherogenic conditions. Methods By the use of RNA interference and genetic deletion, the role of JAM-A in the transmigration of T cells and monocytes through aortic endothelial cells was investigated. JAM-A–localization and subsequent mononuclear cell rolling, adhesion and transmigration were explored during endothelial inflammation, induced by oxidized LDL or cytokines. Results RNA interference or genetic deletion of JAM-A in aortic endothelial cells resulted in a decreased transmigration of mononuclear cells. Treatment of the endothelial cells with oxLDL resulted in an increase of both permeability and apical JAM-A presentation, as shown by bead adhesion and confocal microscopy experiments. Redistribution of JAM-A resulted in an increased leukocyte adhesion and transmigration, which could be inhibited with antibodies against JAM-A or by lovastatin-treatment, but not with the peroxisome proliferator activated receptor gamma-agonist pioglitazone. Conclusions This study demonstrates that redistribution of JAM-A in endothelial cells after stimulation with pro-atherogenic oxidized lipoproteins results in increased transmigration of mononuclear cells. This inflammatory dispersal of JAM-A could be counteracted with statins, revealing a novel aspect of their mechanism of action.

Objective: To investigate whether an adverse body composition is associated with endothelial dysfunction (ED) and the extent to which any such association could be explained by low-grade inflammation (LGI) and/or insulin resistance (HOMA2-IR). Methods: We studied 475 individuals from the Hoorn Study [mean (range) age, 68.9 (60-87) years, 245 women). Body composition was assessed by whole body dual-energy absorptiometry. Endothelial dysfunction was measured functionally, by flow-mediated dilation (FMD) and by circulating biomarkers. Associations were examined with multiple linear regression models and mediation analyses according to the ab product of coefficients method. Results: After adjustment for age, sex, glucose metabolism status, prior cardiovascular disease and lifestyle factors, total and central fat mass were positively associated with the ED score [beta = 0.16 (95% CI 0.04-0.29) and b 0.18 (0.05-0.31), respectively] and inversely, although not statistically significantly, with FMD. Peripheral fat mass was not associated with the ED score or FMD. There was a significant favourable association between peripheral lean mass and FMD [beta = 0.13 (0.00-0.26)], but not with the ED score. The association between total and central fat mass and the ED score was, to a great extent, mediated by LGI and HOMA2-IR. In contrast, LGI or HOMA2-IR did not mediate the association between peripheral lean mass and FMD. Conclusion: Higher levels of central, but not peripheral fat mass were adversely associated with ED, which was attributable to body composition-related LGI and insulin resistance. In contrast, peripheral lean mass was beneficially associated with ED, but this seemed to be unrelated to LGI or insulin resistance. (C) 2014 Elsevier Ireland Ltd. All rights reserved.