Activation of Toll like receptors (TLR) plays an important role in cardiovascular disease development, progression and outcomes. Complex TLR mediated signaling affects vascular and cardiac function... Show moreActivation of Toll like receptors (TLR) plays an important role in cardiovascular disease development, progression and outcomes. Complex TLR mediated signaling affects vascular and cardiac function including tissue remodeling and repair. Being central components of both innate and adaptive arms of the immune system, TLRs interact as pattern recognition receptors with a series of exogenous ligands and endogenous molecules or so-called danger associated molecular patterns (DAMPs) that are released upon tissue injury and cellular stress. Besides immune cells, a number of structural cells within the cardiovascular system, including endothelial cells, smooth muscle cells, fibroblasts and cardiac myocytes express TLRs and are able to release or sense DAMPs. Local activation of TLR-mediated signaling cascade induces cardiovascular tissue repair but in a presence of constant stimuli can overshoot and cause chronic inflammation and tissue damage. TLR accessory molecules are essential in guiding and dampening these responses toward an adequate reaction. Furthermore, accessory molecules assure specific and exclusive TLR-mediated signal transduction for distinct cells and pathways involved in the pathogenesis of cardiovascular diseases. Although much has been learned about TLRs activation in cardiovascular remodeling, the exact role of TLR accessory molecules is not entirely understood. Deeper understanding of the role of TLR accessory molecules in cardiovascular system may open therapeutic avenues aiming at manipulation of inflammatory response in cardiovascular disease. The present review outlines accessory molecules for membrane TLRs that are involved in cardiovascular disease progression. We first summarize the up-to-date knowledge on TLR signaling focusing on membrane TLRs and their ligands that play a key role in cardiovascular system. We then survey the current evidence of the contribution of TLRs accessory molecules in vascular and cardiac remodeling including myocardial infarction, heart failure, stroke, atherosclerosis, vein graft disease and arterio-venous fistula failure. Show less
Voorzaat, B.M.; Bogt, K.E.A. van der; Bezhaeva, T.; Schaik, J. van; Eefting, D.; Putten, K. van der; ... ; Rotmans, J.I. 2020
INTRODUCTION: Maturation failure of radiocephalic arteriovenous fistulas (RCAVF) is a significant clinical issue. Vascular inflammation after AVF surgery is associated with non-maturation.OBJECTIVE... Show moreINTRODUCTION: Maturation failure of radiocephalic arteriovenous fistulas (RCAVF) is a significant clinical issue. Vascular inflammation after AVF surgery is associated with non-maturation.OBJECTIVE: To evaluate whether liposomal prednisolone improves RCAVF maturation in end-stage renal disease (ESRD) patients.DESIGN: The LIPMAT-study was a multi-center, double-blind, 1:1 randomized, placebo-controlled trial.MATERIALS AND METHODS: Subjects were enrolled after RCAVF creation and treated with placebo or 150 mg of liposomal prednisolone at days 1 and 15 after AVF surgery. The primary end point was the juxta-anastomotic diameter of the cephalic vein at 6 weeks after surgery. Secondary end points were the diameter of the cephalic vein, brachial and radial artery at 6 weeks and 3 months after surgery as well as AVF flow and functional use for hemodialysis. Adverse events were compared to assess safety.RESULTS: 29 subjects were included of which 13 received placebo and 16 received liposomal prednisolone. The juxta-anastomitic cephalic vein diameter at 6 weeks was 3.9 mm (95% confidence interval 2.7 – 5.8 mm) in the placebo group and 3.7 mm (95% confidence interval 3.0 – 5.3 mm) in the liposomal prednisolone group (p=0.88). No significant differences in secondary end point parameters were observed. Treatment of end-stage renal disease patients with liposomal prednisolone was not associated with significant side effects.CONCLUSION: Liposomal prednisolone treatment of ESRD patients was safe, but did not result in enhanced RCAVF maturation. Show less
Dysfunction of vascular access remains a major clinical problem responsible for high morbidity and substantial health care costs in patients required chronic hemodialysis treatment. Despite the... Show moreDysfunction of vascular access remains a major clinical problem responsible for high morbidity and substantial health care costs in patients required chronic hemodialysis treatment. Despite the magnitude of this clinical problem, there have been no major novel therapeutic interventions in the field of hemodialysis access for the past few decades. The work described in this thesis aimed to further understand the pathobiology of vascular access dysfunction and identify new therapeutic candidates to improve the current status of hemodialysis vascular access.We first explored the role of inflammation in vascular remodeling upon arteriovenous fistula (AVF) surgery. Based on the evolving concept of the importance of the outward remodeling (OR) in AVF maturation next, we evaluated the role of relaxin pathway as potential contributor to OR in AVF maturation. In parallel with testing new therapeutics to improve maturation and patency of native AVFs, our group is working on developing tissue engineered blood vessels (TEBVs) which could offer a suitable alternative for arteriovenous conduits. In collaboration with University of California, Los Angeles, we performed a lineage tracing to study the contribution of bone marrow derived cells to TEBV formation and the impact of chronic kidney disease onto the process of TEBV formation. Show less
BACKGROUND:Treatment of inflammatory kidney diseases with systemic high-dose glucocorticoids (GCs) has severe side effects. Liposomal encapsulation could facilitate local delivery of GCs to the... Show moreBACKGROUND:Treatment of inflammatory kidney diseases with systemic high-dose glucocorticoids (GCs) has severe side effects. Liposomal encapsulation could facilitate local delivery of GCs to the inflamed kidney, as liposomes encapsulate their payload until extravasation at sites of inflammation, potentially resulting in local bioactivity. Our aim was to evaluate the ability of liposomes to accumulate locally after renal ischaemia-reperfusion injury in the rat and to study its effect on macrophages.METHODS:In vitro, human macrophages were incubated with fluorescent liposomes, liposomal prednisolone, prednisolone, empty liposomes or saline. Uptake was studied microscopically and treatment effect was assessed by interkeukin 6 (IL-6) enzyme-linked immunosorbent assay. The mechanism of action was evaluated by analysing GC receptor activation by microscopy and quantitative polymerase chain reaction (qPCR). In vivo, rats were subjected to ischaemia-reperfusion injury and were injected intravenously with fluorescent liposomes, liposomal prednisolone, prednisolone, empty liposomes or saline. Uptake was measured by the FLARE camera and the treatment effect by immunohistochemistry for myeloid cells and qPCR for inflammatory markers.RESULTS:In vitro, macrophages internalized liposomes after 8 hours. Prednisolone or liposomal prednisolone treatment reduced IL-6 production and both compounds induced translocation of the GC receptor to the nucleus and upregulation of PER1 messenger RNA (mRNA), indicating a similar mechanism of action. In vivo, fluorescent liposomes accumulated in the inflamed kidney. Liposomal prednisolone treatment increased the presence of ED2-positive anti-inflammatory macrophages and both prednisolone and liposomal prednisolone reduced monocyte chemoattractant protein-1 (MCP-1) mRNA production, indicating a reduced pro-inflammatory profile in the kidney.CONCLUSIONS:Liposomal encapsulation is a promising strategy for local delivery of glucocorticoids to the inflamed kidney. Show less
