Inactivation of the tyrosine phosphatase SHP-2 drives vascular dysfunction in Sepsis.

Background: Sepsis, the most severe form of infection, involves endothelial dysfunction which contributes to organ failure. To improve therapeutic prospects, elucidation of molecular mechanisms underlying endothelial vascular failure is of essence.

Methods: Polymicrobial contamination induced sepsis mouse model and primary endothelial cells incubated with sepsis serum were used to study SHP-2 in sepsis-induced endothelial inflammation.

Targeting of Magnetic Nanoparticle-coated Microbubbles to the Vascular Wall Empowers Site-specific Lentiviral Gene Delivery .

In the field of vascular gene therapy, targeting systems are promising advancements to improve site-specificity of gene delivery. Here, we studied whether incorporation of magnetic nanoparticles (MNP) with different magnetic properties into ultrasound sensitive microbubbles may represent an efficient way to enable gene targeting in the vascular system after systemic application. Thus, we associated novel silicon oxide-coated magnetic nanoparticle containing microbubbles (SO-Mag MMB) with lentiviral particles carrying therapeutic genes and determined their physico-chemical as well as biological properties compared to MMB coated with polyethylenimine-coated magnetic nanoparticles (PEI-Mag MMB).

The proteasome regulates collagen-induced platelet aggregation via nuclear-factor-kappa-B (NFĸB) activation.

Introduction: Platelets possess critical hemostatic functions in the system of thrombosis and hemostasis, which can be affected by a multitude of external factors. Previous research has shown that platelets have the capacity to synthesize proteins de novo and more recently a multicatalytic protein complex, the proteasome, has been discovered in platelets. Due to its vital function for cellular integrity, the proteasome has become a therapeutic target for anti-proliferative drug therapies in cancer.

Arterial thrombosis in the context of HCV-associated vascular disease can be prevented by protein C.

Hepatitis C virus (HCV) infection is a major problem worldwide. HCV is not limited to liver disease but is frequently complicated by immune-mediated extrahepatic manifestations such as glomerulonephritis or vasculitis. A fatal complication of HCV-associated vascular disease is thrombosis.

LL37 inhibits the inflammatory endothelial response induced by viral or endogenous DNA.

In viral infection, morbidity and mortality often result from extrahepatic disease manifestations such as vasculitis. We hereby show that human microvascular endothelial cells express viral receptors of the innate immune system which are induced upon ligand engagement. Furthermore, stimulation of endothelial cells with the synthetic analog of viral DNA, poly (dA:dT), human DNA and hepatitis B virus-containing immunoprecipitates from a patient with polyarteritis nodosa induces an inflammatory response including the upregulation of adhesion molecules, which is mediated exclusively by TLR9 and involves an IRF3-dependent pathway.

The tyrosine phosphatase SHP-1 regulates hypoxia inducible factor-1α (HIF-1α) protein levels in endothelial cells under hypoxia.

Introduction: The tyrosine phosphatase SHP-1 negatively influences endothelial function, such as VEGF signaling and reactive oxygen species (ROS) formation, and has been shown to influence angiogenesis during tissue ischemia. In ischemic tissues, hypoxia induced angiogenesis is crucial for restoring oxygen supply. However, the exact mechanism how SHP-1 affects endothelial function during ischemia or hypoxia remains unclear.

Hepatitis C virus induced endothelial inflammatory response depends on the functional expression of TNFα receptor subtype 2.

In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I:C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes.

Myeloperoxidase is not useful for detecting stress inducible myocardial ischemia but may be indicative of the severity of coronary artery disease.

Background And Objectives: Elevated levels of myeloperoxidase (MPO) have been found in patients in different stages of coronary artery disease (CAD). The aim of this study was to assess whether the MPO liberation is increased by stress inducible myocardial ischemia and could be used to improve the diagnostic accuracy of non-invasive evaluation for myocardial ischemia.

Subjects And Methods: Seventy-six patients with suspected myocardial ischemia who underwent stress myocardial perfusion scintigraphy (MPS) were enrolled.

The endothelial tyrosine phosphatase SHP-1 plays an important role for vascular haemostasis in TNFα -induced inflammation in vivo.

Introduction: Inflammation and endothelium-derived superoxides are important pathomechanisms in atherothrombotic diseases. We could previously show that the tyrosine phosphatase SHP-1 acts as a negative regulator in endothelial superoxide production. In this study we investigated the influence of SHP-1 on platelet-endothelium interaction and arterial thrombosis in TNFα -induced endothelial inflammation in vivo.

Prothrombotic effects of tumor necrosis factor alpha in vivo are amplified by the absence of TNF-alpha receptor subtype 1 and require TNF-alpha receptor subtype 2.

Introduction: Elevated serum levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFα) correlate with an increased risk for atherothrombotic events and TNFα is known to induce prothrombotic molecules in endothelial cells. Based on the preexisting evidence for the impact of TNFα in the pathogenesis of autoimmune disorders and their known association with an acquired hypercoagulability, we investigated the effects of TNFα and the role of the TNF receptor subtypes TNFR1 and TNFR2 for arteriolar thrombosis in vivo.

Methods: Arteriolar thrombosis and platelet-rolling in vivo were investigated in wildtype, TNFR1-/-, TNFR2-/- and TNFR1-/R2-/- C57BL/6 mice using intravital microscopy in the dorsal skinfold chamber microcirculation model.

Hydrogen sulfide-releasing aspirin derivative ACS14 exerts strong antithrombotic effects in vitro and in vivo.

Objective: Hydrogen sulfide (H(2)S)-releasing NSAIDs exert potent anti-inflammatory effects beyond classical cyclooxygenase inhibition. Here, we compared the platelet inhibitory effects of the H(2)S-releasing aspirin derivative ACS14 with its mother compound aspirin to analyze additional effects on platelets.

Methods And Results: In platelets of mice fed with ACS14 for 6 days (50 mg/kg per day), not only arachidonic acid-induced platelet aggregation but also ADP-dependent aggregation was decreased, an effect that was not observed with an equimolar dose of aspirin (23 mg/kg per day).

Response of VEGF to activation of viral receptors and TNFα in human mesangial cells.

Vascular endothelial growth factor (VEGF) plays an important role in glomerular homeostasis as well as in the pathogenesis of kidney diseases as glomerulonephritis (GN) and diabetic nephropathy. Mesangial cells (MC), which are an integral part of the functional glomerular filtration barrier in that providing structural support, can behave like inflammatory cells and produce mediators as chemokines and growth factors; they are known to express viral receptors, with TLR3 having been attributed relevance in viral disease-associated GN. Experiments were performed on human MC in cell culture.

SHP-2 regulates growth factor dependent vascular signalling and function.

Cellular responses to the environment are mediated by intracellular signalling pathways monitoring several essential cellular processes, such as proliferation, migration, differentiation and survival. Cellular dysfunction is caused by dysregulation of intracelleular signalling pathways and may ultimately result in pathophysiological conditions. The non- transmembrane protein tyrosine phosphatase SHP-2 has been shown to be important for the control of cellular behaviour.

Site directed vascular gene delivery in vivo by ultrasonic destruction of magnetic nanoparticle coated microbubbles.

Unlabelled: Site specific vascular gene delivery for therapeutic implications is favorable because of reduction of possible side effects. Yet this technology faces numerous hurdles that result in low transfection rates because of suboptimal delivery. Combining ultrasonic microbubble technology with magnetic nanoparticle enhanced gene transfer could make it possible to use the systemic vasculature as the route of application and to magnetically trap these compounds at the target of interest.

Targeted endothelial gene delivery by ultrasonic destruction of magnetic microbubbles carrying lentiviral vectors.

Purpose: Site specific vascular gene delivery is a promising tool for treatment of cardiovascular diseases. By combining ultrasound mediated microbubble destruction with site specific magnetic targeting of lentiviruses, we aimed to develop a technique suitable for systemic application.

Methods: The magnetic nanoparticle coupling to lipid microbubbles was confirmed by absorbance measurements.

ARNO regulates VEGF-dependent tissue responses by stabilizing endothelial VEGFR-2 surface expression.

Aims: The vascular endothelial growth factor (VEGF) stimulates angiogenesis by induction of vessel permeability, proliferation, and migration of endothelial cells, an important process in ischaemic diseases. ADP-ribosylation factor (ARF) nucleotide-binding site opener (ARNO) (cytohesin-2) is a guanine exchange factor important for cellular signalling through ARF GTPases. However, a role for ARNO in VEGF-dependent endothelial processes has so far not been documented.

Five-year clinical follow-up after sirolimus-eluting stent implantation for the treatment of coronary in-stent restenosis.

Background: Late vessel failure by restenosis or thrombosis is a potential limitation of drug-eluting stent implantation.

Methods: We conducted a prospective 5-year clinical evaluation following implantation of sirolimus-eluting Cypher stents for in-stent restenosis regardless of the patient's symptomatic status. A complete 5-year follow-up is reported for 192 consecutive patients.

Late and very late catch-up after 90Sr/90Y beta-irradiation for the treatment of coronary in-stent restenosis.

Since late vessel failure has been speculated as a significant limitation of vascular brachytherapy (VBT), we conducted a prospective clinical evaluation at 6, 12, 24, 36 and 60 months follow-up after irradiation with (90)Sr/(90)Y for in-stent restenosis (ISR) regardless of the patient's symptomatic status. Complete five-year follow-up is reported for 104 consecutive patients. The cumulative rate of death was 13.

Bioactivation of dermal scaffolds with a non-viral copolymer-protected gene vector.

The use of scaffolds in skin tissue engineering is accompanied with low regeneration rates and high risk of infection. In this study, we activated an FDA-approved collagen scaffold for dermal regeneration by incorporation of copolymer-protected gene vectors (COPROGs) to induce a temporary release of VEGF. In vitro results show that the presence of COPROGs did not affect the distribution, attachment, proliferation and viability of cells in the scaffold.

CD34+CD140b+ cells and circulating CXCL12 correlate with the angiographically assessed severity of cardiac allograft vasculopathy.

Aims: We sought to determine whether circulating vascular progenitor cells, such as endothelial progenitor cells (EPCs) or smooth muscle progenitor cells (SPCs), were associated with the severity of cardiac allograft vasculopathy (CAV).

Methods And Results: CD34(+)CD140b(+) SPCs and CD34(+)KDR(+) EPCs were measured in the peripheral circulation of 187 adult heart transplant recipients by flow cytometry. Cardiac allograft vasculopathy was quantified by angiography using a CAV-specific scoring system.