CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species

Background— The CD40/CD40 ligand system is involved in atherogenesis. Activated T lymphocytes and platelets, which express high amounts of CD40 ligand (CD40L) on their surface, contribute significantly to plaque instability with ensuing thrombus formation, leading to acute coronary syndromes. Because reendothelialization may play a pivotal role for plaque stabilization, we investigated a potential role of CD40L on endothelial cell (EC) migration

Different approaches to community detection

A precise definition of what constitutes a community in networks has remained elusive. Consequently, network scientists have compared community detection algorithms on benchmark networks with a particular form of community structure and classified them based on the mathematical techniques they employ. However, this comparison can be misleading because apparent similarities in their mathematical machinery can disguise different reasons for why we would want to employ community detection in the first place. Here we provide a focused review of these different motivations that underpin community detection. This problem-driven classification is useful in applied network science, where it is important to select an appropriate algorithm for the given purpose. Moreover, highlighting the different approaches to community detection also delineates the many lines of research and points out open directions and avenues for future research.Comment: 14 pages, 2 figures. Written as a chapter for forthcoming Advances in network clustering and blockmodeling, and based on an extended version of The many facets of community detection in complex networks, Appl. Netw. Sci. 2: 4 (2017) by the same author

Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells

Background— Transplantation of ex vivo expanded circulating endothelial progenitor cells (EPCs) from peripheral blood mononuclear cells improves the neovascularization after critical ischemia. However, the origin of the endothelial progenitor lineage and its characteristics have not yet been clearly defined. Therefore, we investigated whether the phenotype and functional capacity of EPCs to improve neovascularization depend on their monocytic origin

Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia

Background— Stem and progenitor cell therapy is a novel approach to improve neovascularization and function of ischemic tissue. Enhanced tissue expression of chemoattractant factors such as stromal cell–derived factor 1 and vascular endothelial growth factor is crucial for the recruitment of circulating endothelial progenitor cells (EPCs) during acute ischemia. In chronic ischemia, however, expression of these chemoattractants is less pronounced, which results in insufficient EPC recruitment into the target tissue. Therefore, we investigated the effect of targeted extracorporeal shock wave (SW) application in order to facilitate EPC recruitment into nonischemic and chronic ischemic tissue

Nicotine strongly activates dendritic cell-mediated adaptive immunity - potential role for progression of atherosclerotic lesions

Background - Antigen-presenting cells (APCs) such as monocytes and dendritic cells (DCs) stimulate T-cell proliferation and activation in the course of adaptive immunity. This cellular interaction plays a role in the growth of atherosclerotic plaques. Nicotine has been shown to increase the growth of atherosclerotic lesions. Therefore, we investigated whether nicotine can stimulate APCs and their T cell–stimulatory capacity using human monocyte–derived DCs and murine bone marrow–derived DCs as APCs. Methods and Results - Nicotine dose-dependently (10-8 to 10-4 mol/L) induced DC expression of costimulatory molecules (ie, CD86, CD40), MHC class II, and adhesion molecules (ie, LFA-1, CD54). Moreover, nicotine induced a 7.0-fold increase in secretion of the proinflammatory TH1 cytokine interleukin-12 by human DCs. These effects were abrogated by the nicotinic receptor antagonist -bungarotoxin and mecamylamine, respectively. The effects of nicotine were mediated in part by the phosphorylation of the PI3 kinase downstream target Akt and the mitogen-activated kinases ERK and p38 MAPK. Nicotine-stimulated APCs had a greater capacity to stimulate T-cell proliferation and cytokine secretion, as documented by mixed lymphocyte reactions and ovalbumin-specific assays with ovalbumin-transgenic DO10.11 mice. In a murine model of atherosclerosis, nicotine significantly enhanced the recruitment of DCs to atherosclerotic lesions in vivo. Conclusions - Nicotine activates DCs and augments their capacity to stimulate T-cell proliferation and cytokine secretion. These effects of nicotine may contribute to its influence on the progression of atherosclerotic lesions

Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease

Background - Therapeutic neovascularization may constitute an important strategy to salvage tissue from critical ischemia. Circulating bone marrow–derived endothelial progenitor cells (EPCs) were shown to augment the neovascularization of ischemic tissue. In addition to lipid-lowering activity, hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) reportedly promote the neovascularization of ischemic tissue in normocholesterolemic animals. Methods and Results - Fifteen patients with angiographically documented stable coronary artery disease (CAD) were prospectively treated with 40 mg of atorvastatin per day for 4 weeks. Before and weekly after the initiation of statin therapy, EPCs were isolated from peripheral blood and counted. In addition, the number of hematopoietic precursor cells positive for CD34, CD133, and CD34/kinase insert domain receptor was analyzed. Statin treatment of patients with stable CAD was associated with an '1.5-fold increase in the number of circulating EPCs by 1 week after initiation of treatment; this was followed by sustained increased levels to '3-fold throughout the 4-week study period. Moreover, the number of CD34/kinase insert domain receptor–positive hematopoietic progenitor cells was significantly augmented after 4 weeks of therapy. Atorvastatin treatment increased the further functional activity of EPCs, as assessed by their migratory capacity

The role of toll-like receptors (TLRs) in bacteria-induced maturation of murine dendritic cells (DCs) - Peptidoglycan and lipoteichoic acid are inducers of DC maturation and require TLR2

Toll-like receptors (TLRs) have been found to be key elements in pathogen recognition by the host immune system. Dendritic cells (DCs) are crucial for both innate immune responses and initiation of acquired immunity. Here we focus on the potential involvement of TLR ligand interaction in DC maturation. TLR2 knockout mice and mice carrying a TLR4 mutation (C3H/HeJ) were investigated for DC maturation induced by peptidoglycan (PGN), lipopolysaccharide (LPS), or lipoteichoic acids (LTAs). All stimuli induced maturation of murine bone marrow-derived DCs in control mice. TLR2− /− mice lacked maturation upon stimulation with PGN, as assessed by expression of major histocompatibility complex class II, CD86, cytokine, and chemokine production, fluorescein isothiocyanate-dextran uptake, and mixed lymphocyte reactions, while being completely responsive to LPS. A similar lack of maturation was observed in C3H/HeJ mice upon stimulation with LPS. DC maturation induced by LTAs from two different types of bacteria was severely impaired in TLR2− /−, whereas C3H/HeJ mice responded to LTAs in a manner similar to wild-type mice. We demonstrate that DC maturation is induced by stimuli from Gram-positive microorganisms, such as PGN and LTA, with similar efficiency as by LPS. Finally, we provide evidence that TLR2 and TLR4 interaction with the appropriate ligand is essential for bacteria-induced maturation of DCs

Vitamin C inhibits endothelial cell apoptosis in congestive heart failure

Background - Proinflammatory cytokines like tumor necrosis factor- and oxidative stress induce apoptotic cell death in endothelial cells (ECs). Systemic inflammation and increased oxidative stress in congestive heart failure (CHF) coincide with enhanced EC apoptosis and the development of endothelial dysfunction. Therefore, we investigated the effects of antioxidative vitamin C therapy on EC apoptosis in CHF patients. Methods and Results - Vitamin C dose dependently suppressed the induction of EC apoptosis by tumor necrosis factor- and angiotensin II in vitro as assessed by DNA fragmentation, DAPI nuclear staining, and MTT viability assay. The antiapoptotic effect of vitamin C was associated with reduced cytochrome C release from mitochondria and the inhibition of caspase-9 activity. To assess EC protection by vitamin C in CHF patients, we prospectively randomized CHF patients in a double-blind trial to vitamin C treatment versus placebo. Vitamin C administration to CHF patients markedly reduced plasma levels of circulating apoptotic microparticles to 32±8% of baseline levels, whereas placebo had no effect (87±14%, P<0.005). In addition, vitamin C administration suppressed the proapoptotic activity on EC of the serum of CHF patients (P<0.001). Conclusions - Administration of vitamin C to CHF patients suppresses EC apoptosis in vivo, which might contribute to the established functional benefit of vitamin C supplementation on endothelial function

Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease

Background— Cell therapy with bone marrow–derived stem/progenitor cells is a novel option for improving neovascularization and cardiac function in ischemic heart disease. Circulating endothelial progenitor cells in patients with coronary heart disease are impaired with respect to number and functional activity. However, whether this impairment also extends to bone marrow–derived mononuclear cells (BM-MNCs) in patients with chronic ischemic cardiomyopathy (ICMP) is unclea

Tumor necrosis factor-alpha regulates the expression of inducible costimulator receptor ligand on CD34+ progenitor cells during differentiation into antigen presenting cells

The inducible costimulator receptor (ICOS) is a third member of the CD28 receptor family that regulates T cell activation and function. ICOS binds to a newly identified ligand on antigen presenting cells different from the CD152 ligands CD80 and CD86. We used soluble ICOSIg and a newly developed murine anti-human ICOS ligand (ICOSL) monoclonal antibody to further characterize the ICOSL during ontogeny of antigen presenting cells. In a previous study, we found that ICOSL is expressed on monocytes, dendritic cells, and B cells. To define when ICOSL is first expressed on myeloid antigen presenting cells, we examined ICOSL expression on CD34 cells in bone marrow. We found that CD34bright cells regardless of their myeloid commitment were ICOSL , whereas ICOSL was first expressed when CD34 expression diminished and the myeloid marker CD33 appeared