Endothelial Dysfunction, Atherosclerosis, and Increase of von Willebrand Factor and Factor VIII: A Randomized Controlled Trial in Swine.

It is well known that high von Willebrand factor (VWF) and factor VIII (FVIII) levels are associated with an increased risk of cardiovascular disease. It is still debated whether VWF and FVIII are biomarkers of endothelial dysfunction and atherosclerosis or whether they have a direct causative role. Therefore, we aimed to unravel the pathophysiological pathways of increased VWF and FVIII levels associated with cardiovascular risk factors.

Whole-Mount Immunofluorescence Staining, Confocal Imaging and 3D Reconstruction of the Sinoatrial and Atrioventricular Node in the Mouse.

The electrical signal physiologically generated by pacemaker cells in the sinoatrial node (SAN) is conducted through the conduction system, which includes the atrioventricular node (AVN), to allow excitation and contraction of the whole heart. Any dysfunction of either SAN or AVN results in arrhythmias, indicating their fundamental role in electrophysiology and arrhythmogenesis. Mouse models are widely used in arrhythmia research, but the specific investigation of SAN and AVN remains challenging.

Isolation of High Quality Murine Atrial and Ventricular Myocytes for Simultaneous Measurements of Ca2+ Transients and L-Type Calcium Current.

Mouse models play a crucial role in arrhythmia research and allow studying key mechanisms of arrhythmogenesis including altered ion channel function and calcium handling. For this purpose, atrial or ventricular cardiomyocytes of high quality are necessary to perform patch-clamp measurements or to explore calcium handling abnormalities. However, the limited yield of high-quality cardiomyocytes obtained by current isolation protocols does not allow both measurements in the same mouse.

The Role of Connexin 43 and Pannexin 1 During Acute Inflammation.

During acute inflammation, the recruitment of leukocytes from the blood stream into the inflamed tissue is a well-described mechanism encompassing the interaction of endothelial cells with leukocytes allowing leukocytes to reach the site of tissue injury or infection where they can fulfill their function such as phagocytosis. This process requires a fine-tuned regulation of a plethora of signaling cascades, which are still incompletely understood. Here, connexin 43 (Cx43) and pannexin 1 (Panx1) are known to be pivotal for the correct communication of endothelial cells with leukocytes.

Structure and Emerging Functions of LRCH Proteins in Leukocyte Biology.

Actin-dependent leukocyte trafficking and activation are critical for immune surveillance under steady state conditions and during disease states. Proper immune surveillance is of utmost importance in mammalian homeostasis and it ensures the defense against pathogen intruders, but it also guarantees tissue integrity through the continuous removal of dying cells or the elimination of tumor cells. On the cellular level, these processes depend on the precise reorganization of the actin cytoskeleton orchestrating, e.

Purinergic Dysfunction in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which result in an increase in afterload imposed onto the right ventricle, leading to right heart failure. Current therapies are incapable of reversing the disease progression. Thus, the identification of novel and potential therapeutic targets is urgently needed.

Coronin 1B Controls Endothelial Actin Dynamics at Cell-Cell Junctions and Is Required for Endothelial Network Assembly.

Development and homeostasis of blood vessels critically depend on the regulation of endothelial cell-cell junctions. VE-cadherin (VEcad)-based cell-cell junctions are connected to the actin cytoskeleton and regulated by actin-binding proteins. Coronin 1B (Coro1B) is an actin binding protein that controls actin networks at classical lamellipodia.

Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement.

The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model.

Principles of Leukocyte Migration Strategies.

Migration of leukocytes is essential for the induction, maintenance, and regulation of immune responses. On their trafficking routes, leukocytes encounter microenvironments of diverse mechanochemical composition, such as epithelial sheets, fibrillar networks, and cell-dense lymphatic organs. These microenvironments impose fundamental challenges on leukocytes, which include adhesive crawling under high shear stress, extreme cellular deformation while crossing physical barriers, and pathfinding in maze-like 3D environments.

Impact of carbohydrate-reduced nutrition in septic patients on ICU: study protocol for a prospective randomised controlled trial.

Introduction: Sepsis is defined as detrimental immune response to an infection. This overwhelming reaction often abolishes a normal reconstitution of the immune cell homeostasis that in turn increases the risk for further complications. Recent studies revealed a favourable impact of ketone bodies on resolution of inflammation.

Pig-to-non-human primate heart transplantation: The final step toward clinical xenotransplantation?

Background: The demand for donated human hearts far exceeds the number available. Xenotransplantation of genetically modified porcine organs provides an alternative. In 2000, an Advisory Board of the International Society for Heart and Lung Transplantation set the benchmark for commencing clinical cardiac xenotransplantation as consistent 60% survival of non-human primates after life-supporting porcine heart transplantations.

l-Tryptophan-Induced Vasodilation Is Enhanced in Preeclampsia: Studies on Its Uptake and Metabolism in the Human Placenta.

l-tryptophan induces IDO (indoleamine 2,3-dioxygenase) 1-dependent vasodilation. IDO1 is expressed in placental endothelial cells and downregulated in preeclampsia. Hypothesizing that this may contribute to diminished placental perfusion, we studied l-tryptophan-induced vasodilation in healthy and early-onset preeclampsia placental arteries, focusing on placental kynurenine pathway alterations.

Microtubules control cellular shape and coherence in amoeboid migrating cells.

Cells navigating through complex tissues face a fundamental challenge: while multiple protrusions explore different paths, the cell needs to avoid entanglement. How a cell surveys and then corrects its own shape is poorly understood. Here, we demonstrate that spatially distinct microtubule dynamics regulate amoeboid cell migration by locally promoting the retraction of protrusions.

Both male and female obese ZSF1 rats develop cardiac dysfunction in obesity-induced heart failure with preserved ejection fraction.

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts.

Lower Plasma Melatonin Levels Predict Worse Long-Term Survival in Pulmonary Arterial Hypertension.

Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve patients with PH and their clinical significance are still unknown.

Perturbations in myocardial perfusion and oxygen balance in swine with multiple risk factors: a novel model of ischemia and no obstructive coronary artery disease.

Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD). Increasing evidence suggests that CMD may contribute to myocardial 'Ischemia and No Obstructive Coronary Artery disease' (INOCA). In the present study, we tested the hypothesis that CMD results in perturbations in myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities.

The IL-1 Antagonist Anakinra Attenuates Glioblastoma Aggressiveness by Dampening Tumor-Associated Inflammation.

Background: The recombinant IL-1 receptor antagonist anakinra-currently approved for the treatment of autoinflammatory diseases-blocks IL-1β-mediated inflammatory signaling. As inflammation is a major driver of cancer, we hypothesized that anakinra might be able to mitigate glioblastoma (GBM) aggressiveness.

Methods: Primary GBM or T98G cells were incubated alone or with peripheral blood mononuclear cells (PBMCs) and were subsequently treated with IL-1β and/or anakinra.

Desensitization of transient receptor potential vanilloid type-1 (TRPV1) channel as promising therapy of irritable bowel syndrome: characterization of the action of palvanil in the mouse gastrointestinal tract.

TRPV1 are involved in the control of the gastrointestinal (GI) functions and pain sensation. Their activation induces pain but it is followed by desensitization, which in turn causes analgesia. The studies from the last two decades indicate that TRPV1 are involved in visceral hypersensitivity in the GI tract and pathogenesis of irritable bowel syndrome (IBS).

Neutrophils as emerging therapeutic targets.

Neutrophils are the most abundant circulating leukocytes, being the first line of defence against bacterial and fungal infections. However, neutrophils also contribute to tissue damage during various autoimmune and inflammatory diseases, and play important roles in cancer progression. The intimate but complex involvement of neutrophils in various diseases makes them exciting targets for therapeutic intervention but also necessitates differentiation of beneficial responses from potentially detrimental side effects.

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells.

Molecular imaging is essential for diagnosis and treatment planning for glioblastoma patients. Positron emission tomography (PET) with tracers for the detection of the solute carrier family 7 member 5 (; also known as the amino acid transporter light chain L system, LAT1) and for the mitochondrial translocator protein (TSPO) is successfully used to provide additional information on tumor volume and prognosis. The current approaches for TSPO-PET and the visualization of tracer ([18F] Fluoroethyltyrosine, FET) uptake by LAT1 (FET-PET) do not yet exploit the full diagnostic potential of these molecular imaging techniques.

Porcine models for studying complications and organ crosstalk in diabetes mellitus.

The worldwide prevalence of diabetes mellitus and obesity is rapidly increasing not only in adults but also in children and adolescents. Diabetes is associated with macrovascular complications increasing the risk for cardiovascular disease and stroke, as well as microvascular complications leading to diabetic nephropathy, retinopathy and neuropathy. Animal models are essential for studying disease mechanisms and for developing and testing diagnostic procedures and therapeutic strategies.

The Extraordinary Role of Extracellular RNA in Arteriogenesis, the Growth of Collateral Arteries.

Arteriogenesis is an intricate process in which increased shear stress in pre-existing arteriolar collaterals induces blood vessel expansion, mediated via endothelial cell activation, leukocyte recruitment and subsequent endothelial and smooth muscle cell proliferation. Extracellular RNA (eRNA), released from stressed cells or damaged tissue under pathological conditions, has recently been discovered to be liberated from endothelial cells in response to increased shear stress and to promote collateral growth. Until now, eRNA has been shown to enhance coagulation and inflammation by inducing cytokine release, leukocyte recruitment, and endothelial permeability, the latter being mediated by vascular endothelial growth factor (VEGF) signaling.

Disentangling the Gordian knot of local metabolic control of coronary blood flow.

Recognition that coronary blood flow is tightly coupled with myocardial metabolism has been appreciated for well over half a century. However, exactly how coronary microvascular resistance is tightly coupled with myocardial oxygen consumption (MV̇o) remains one of the most highly contested mysteries of the coronary circulation to this day. Understanding the mechanisms responsible for local metabolic control of coronary blood flow has been confounded by continued debate regarding both anticipated experimental outcomes and data interpretation.