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Objectives The co-stimulatory CD40L–CD40 dyad exerts a critical role in atherosclerosis by modulating leukocyte accumulation into developing atherosclerotic plaques. The requirement for cell-type specific expression of both molecules, however, remains elusive. Here, we evaluate the contribution of CD40 expressed on endothelial cells (ECs) in a mouse model of atherosclerosis. Methods and Results Atherosclerotic plaques of apolipoprotein E-deficient (Apoe −/− ) mice and humans displayed increased expression of CD40 on ECs compared with controls. To interrogate the role of CD40 on ECs in atherosclerosis, we induced EC-specific (BmxCreERT2-driven) deficiency of CD40 in Apoe −/− mice. After feeding a chow diet for 25 weeks, EC-specific deletion of CD40 (iEC-CD40) ameliorated plaque lipid deposition and lesional macrophage accumulation but increased intimal smooth muscle cell and collagen content, while atherosclerotic lesion size did not change. Leukocyte adhesion to the vessel wall was impaired in iEC-CD40-deficient mice as demonstrated by intravital microscopy. In accord, expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in the vascular endothelium declined after deletion of CD40. In vitro, antibody-mediated inhibition of human endothelial CD40 significantly abated monocyte adhesion on ECs. Conclusion Endothelial deficiency of CD40 in mice promotes structural features associated with a stable plaque phenotype in humans and decreases leukocyte adhesion. These results suggest that endothelial-expressed CD40 contributes to inflammatory cell migration and consecutive plaque formation in atherogenesis.

The intent of this report is to describe the technical details and rationale of endovascular septectomy using a wire saw maneuver in cases of chronic aortic dissection and associated infra-renal aortic aneurysm to allow standard endovascular abdominal aortic graft placement; preliminary clinical experience is also retrospectively reviewed.Between June 2013 and June 2016, four consecutive patients (mean age 55.3 years; range 52-58 years) with chronic type B aortic dissection and isolated infra-renal abdominal aortic aneurysm (AAA) underwent endovascular aneurysm repair (EVAR) following guidewire septectomy to create a suitable proximal aortic landing zone. Technical success was evaluated by angiography performed at the end of the procedure. Procedural safety was determined by assessing any major adverse events through 30 days of follow-up. Endoleaks and longer-term efficacy were evaluated.Four patients with chronic aortic dissections had associated AAA with a mean maximum diameter of 60 ± 13 mm (range 50-77 mm). All underwent guidewire saw septectomy to facilitate EVAR. Following successful septectomy, standard abdominal bifurcated endografts were implanted uneventfully. No major adverse events and no endoleaks were noted on CT angiographic examinations through 30 days following the procedure. Also, no rupture, re-intervention or endoleak has been noted during follow-up at a mean of 21.8 ± 15 months (range 4-39 months).Guidewire saw septectomy is a technique that has the potential to create an anatomically suitable proximal neck for successful EVAR management of AAA in select patients with associated chronic aortic dissection.

Diabetes worsens atherosclerosis progression and leads to a defect in repair of arteries after cholesterol reduction, a process termed regression. Empagliflozin reduces blood glucose levels via inhibition of the sodium glucose cotransporter 2 (SGLT-2) in the kidney and has been shown to lead to a marked reduction in cardiovascular events in humans. To determine whether glucose lowering by empagliflozin accelerates atherosclerosis regression in a mouse model, male C57BL/6J mice were treated intraperitoneally with LDLR- and SRB1- antisense oligonucleotides and fed a high cholesterol diet for 16 weeks to induce severe hypercholesterolemia and atherosclerosis progression. At week 14 all mice were rendered diabetic by streptozotocin (STZ) injections. At week 16 a baseline group was sacrificed and displayed substantial atherosclerosis of the aortic root. In the remaining mice, plasma cholesterol was lowered by switching to chow diet and treatment with LDLR sense oligonucleotides to induce atherosclerosis regression. These mice then received either empagliflozin or vehicle for three weeks. Atherosclerotic plaques in the empagliflozin treated mice were significantly smaller, showed decreased lipid and CD68+ macrophage content, as well as greater collagen content. Proliferation of plaque resident macrophages and leukocyte adhesion to the vascular wall were significantly decreased in empagliflozin-treated mice. In summary, plasma glucose lowering by empagliflozin improves plaque regression in diabetic mice.

Introduction Many clinical and experimental observations have established an association between visceral obesity and chronic adipose tissue inflammation. Potent pro-inflammatory mediators such as TNFα, CD40 and IL-1β are regulated by Tumor necrosis factor (TNF) receptor-associated factors (TRAFs). TRAF5 deficiency accelerates atherogenesis in mice by increasing inflammatory leukocyte recruitment. Since inflammatory cell invasion is also a prerequisite of adipose tissue inflammation, we tested the hypothesis that deficient TRAF5 signaling aggravates adipose tissue inflammation and its metabolic complications in a murine diet-induced obesity (DIO) model. Purpose We aimed to clarify the role of TRAF5 in adipose tissue inflammation and metabolic syndrome. Methods TRAF5−/− mice and gender- and age-matched wild-type (WT) mice consumed a high fat diet (HFD, 45%kcal from fat) or a matched low-fat diet (LFD, 10%kcal from fat) for 18 weeks to induce DIO and adipose tissue inflammation. All mice were then subjected to subsequent analysis, including glucose and insulin tolerance testing, body composition assessment by MRI imaging, flow cytometry, gene expression of different tissues, plasma analysis and histology. Finally, we studied if TRAF5 expression was associated with metabolic syndrome in humans by analyzing plasma and adipocytes samples from 62 patients of the Tumor-Necrosis-Factor Receptor Associated in Cardiovascular Risk Study (TRAFICS). Results TRAF5 expression was significantly attenuated in isolated WT-adipocytes and WT-macrophages after 18 weeks of HFD compared to LFD-fed controls. TRAF5−/− mice on HFD gained significantly more weight compared to TRAF5-competent mice and showed an aggravated metabolic phenotype, including impaired insulin tolerance, hyperinsulinemia and increased fasting glucose plasma levels. The weight gain in TRAF5−/− mice was attributable to a significant increase in adipose tissue and liver weight. Further analysis of the visceral adipose tissue revealed enhanced macrophage accumulation and increased pro-inflammatory CD11c+ subset polarization in HFD-fed TRAF5−/− mice. In line with an increased migratory capacity of inflammatory cells, we observed enhanced peritoneal invasion of leukocytes and subsets in TRAF5−/− mice. Accordingly, TRAF5 deficiency increased inflammatory cytokine expression and ameliorated parameters of insulin sensitivity in adipose tissue. Finally, patients with metabolic syndrome displayed decreased TRAF5 expression in blood and adipocytes compared to humans without metabolic syndrome. Conclusion We show that genetic deficiency of TRAF5 aggravates metabolic syndrome in murine diet-induced obesity. Enhanced accumulation of leukocytes subsets in adipose tissue serves as the likely mechanism. We conclude that TRAF5 signaling properties may favorably affect metabolic disease. Acknowledgement/Funding Forschungskommission Medizinische Fakultät Universität Freiburg, MOTI-VATE Promotionskolleg der Medizinischen Fakultät Freiburg (EKFS)

Objective: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor–associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5 −/− mice consumed a high-fat diet for 18 weeks. Traf5 −/− mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5 −/− mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5 −/− mice revealed an increase in cytotoxic T cells, CD11c + macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNFα, MIP (macrophage inflammatory protein)-1α, MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5 -deficient adipocytes but not in Traf5 -deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. Conclusions: We show that a genetic deficiency of TRAF5 in mice aggravates diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.