Vessel Wall Damage Research Articles

Hubungan Merokok dengan Penyakit Jantung Koroner di RSUD Prof. DR. W. Z. Johannes Kupang

A coronary heart disease is a disease which occurs because of the damage of blood vessel walls due to several factors of risk, such as free radical substances contained in cigarettes and pollution, cholesterol, hypertension, and smoking habits. The purpose of this study is to determine the correlation of smoking with coronary heart diseases. The research is an analytic survey with case control design. The population of this study were people who smoke that suffer from coronary heart diseases and those who do not suffer from the diseases. The sampling technique used in this study was simple random sampling, which consisted of 86 respondents. The respondents were divided into case and control sample respondents with similar number of people (43) respectively. The statistical test used was contingency coefficient test (c). The research shows that there was no correlation between jobs and family members health history towards the coronary heart diseases(p>0.05), whereas a correlation was found between the type of cigarettes, smoking intensity, sexes, duration of smoking, and the early age when smoking began with coronary heart diseases (p˂0.05).

Biochemical and immunocytochemical characterization of coronins in platelets

Rapid reorganization of the actin cytoskeleton in response to receptor-mediated signaling cascades allows platelets to transition from a discoid shape to a flat spread shape upon adhesion to damaged vessel walls. Coronins are conserved regulators of the actin cytoskeleton turnover but they also participate in signaling events. To gain a better picture of their functions in platelets we have undertaken a biochemical and immunocytochemical investigation with a focus on Coro1. We found that class I coronins Coro1, 2 and 3 are abundant in human and mouse platelets whereas little Coro7 can be detected. Coro1 is mainly cytosolic, but a significant amount associates with membranes in an actin-independent manner and does not translocate from or to the membrane fraction upon exposure to thrombin, collagen or prostacyclin. Coro1 rapidly translocates to the Triton insoluble cytoskeleton upon platelet stimulation with thrombin or collagen. Coro1, 2 and 3 show a diffuse cytoplasmic localization with discontinuous accumulation at the cell cortex and actin nodules of human platelets, where all three coronins colocalize. Our data are consistent with a role of coronins as integrators of extracellular signals with actin remodeling and suggests a high extent of functional overlap among class I coronins in platelets.

Platelet Activation State Intermixing in a Venous Puncture Model Indicates Novel Patterns of Thrombus Formation

No relevant conflicts of interest to declare.

P2798Final 5-year outcomes of the TRIAS High Risk of Restenosis; a multi-centre, randomized trial comparing endothelial progenitor cell capturing stent with drug-eluting stents

Abstract Background One of the major long-term disadvantages of percutaneous coronary intervention (PCI) remains in-stent restenosis and need for repeat revascularisation. The polymer-regulated delivery of cytotoxic or cytostatic drugs, on drug-eluting stents (DES), impede the natural healing response of the damaged vessel wall. In animals, endothelial progenitor cells (EPCs) beneficially influence the repair of the coronary vessel wall after damage by stent placement. It is hypothesized that after immobilisation the EPCs differentiate into a functional endothelial layer and that this layer will prevent neointimal proliferation and thrombus formation. Anti-CD34+ antibodies are able to capture the EPCs. The Genous stent consist of a bare-metal stent with anti-CD34+ antibody coating. Purpose Demonstrating long-term performance of Genous EPC capturing stent (ECS) relative to DES regarding target lesion failure (TLF); the composite of cardiac death, myocardial infarction (MI) and any target lesion revascularisation (TLR) within 5 years. Methods We undertook an international, clinical trial in 26 centres planning to randomise 1300 patients with stable coronary artery disease and with a high risk of restenosis between treatment with either ECS or DES. After a routine review with 50% of the patients enrolled, early cessation of the trial was recommended by the data and safety monitoring board when TLF in the ECS population was substantially higher and treatment of new patients with an ECS would be unreasonable. The trial was terminated for safety reasons. Results A total of 622 were randomly assigned to receive either Genous ECS (304 patients, 367 lesions) or DES (318 patients, 388 lesions). Five year follow-up data was obtained in 95.5% of patients. TLF occurred in 29.1% of the ECS-treated patients and in 16.0% of the DES-treated patients (p<0.001) (Figure 1). This difference was driven by higher rates of TLR (22.9% vs. 10.7%, p<0.001), but not by cardiac death (6.5% vs. 4.5%, p=0.268), or MI (5.8% vs. 3.6%, p=0.175). Definite or probable stent thrombosis was seen in 8 ECS-treated patients (2.7%) and in 3 DES-treated patients (1%), p=0.11. Figure 1. KM curves of TLF at 5year fu. Conclusion The Genous ECS is not sufficiently strong to compete with DES in terms of restenosis prevention in patients/lesions with a high risk of restenosis. If the addition of a EPCs capturing layer on a DES, like the COMBO stent, provides a lower risk of restenosis compared to DES will be tested in the ongoing SORT-OUT X trial. Acknowledgement/Funding OrbusNeich

Boundary element model for investigation of the effects of various porous baffles on liquid sloshing in the two dimensional rectangular tank

The liquid sloshing resonance may cause the structural instability even damage of vessel walls. The porous baffles have the ability to dissipate the energy of sloshing motion and suppress the sloshing force on the container walls. The liquid is assumed to be incompressible and inviscid, oscillations amplitudes of liquid are treated to be small, and the walls of tank are chosen as rigid. The fluid domain should be divided into several regions by the porous baffles and the virtual boundaries. The fluxes across those porous baffles satisfy continuity, and the difference of pressure between each baffle's sides is linearly proportional to the flow velocity through the baffles. The porous baffles are fixed at the container in this paper, and the external excitation acting on the porous baffles with flow velocity form also should be added to the boundary conditions. Meanwhile, the normal velocity and pressure of virtual boundary named matching boundary between each region sides should remain continuous. The boundary element method (BEM) with Green's theorem based on the potential flow is conducted with the governing equation and the corresponding to the boundaries of each region. The final entire equation of liquid motion is formulated by assembling the equation of each region. The numerical model is validated by comparing the results with those of the available literatures, good agreement is achieved. The results are proposed for the two dimensional rectangular tank with the top or bottom-mounted vertical porous baffles, multiple mounted two-sided porous baffles, middle-mounted circle porous baffle, top or bottom-mounted semicircle porous baffles, top or bottom-mounted T-shaped porous baffle, and center-mounted cosine-shaped porous baffle. The effects of the porous baffle length, porosity and design on the sloshing force, wave surface elevation, and velocity field are studied and some conclusions are obtained.

Interrelationships between structure and function during the hemostatic response to injury

Extensive studies have detailed the molecular regulation of individual components of the hemostatic system, including platelets, coagulation factors, and regulatory proteins. Questions remain, however, about how these elements are integrated at the systems level within a rapidly changing physical environment. To answer some of these questions, we developed a puncture injury model in mouse jugular veins that combines high-resolution, multimodal imaging with functional readouts in vivo. The results reveal striking spatial regulation of platelet activation and fibrin formation that could not be inferred from studies performed ex vivo. As in the microcirculation, where previous studies have been performed, gradients of platelet activation are readily apparent, as is an asymmetrical distribution of fibrin deposition and thrombin activity. Both are oriented from the outer to the inner surface of the damaged vessel wall, with a greater extent of platelet activation and fibrin accumulation on the outside than the inside. Further, we show that the importance of P2Y12 signaling in establishing a competent hemostatic plug is related to the size of the injury, thus limiting its contribution to hemostasis to specific physiologic contexts. Taken together, these studies offer insights into the organization of hemostatic plugs, provide a detailed understanding of the adverse bleeding associated with a widely prescribed class of antiplatelet agents, and highlight differences between hemostasis and thrombosis that may suggest alternative therapeutic approaches.

Using IVUS to improve treatment of complex lesions in the femoropopliteal arteries

Despite rapid advances in in peripheral endovascular therapy over the last 15 years, the rate of restenosis and revascularization in the femoropopliteal arteries remains high. This is particularly the case for more complex lesions, such as longer lesions, those with severe calcification and chronic total occlusions (CTO). The recognised limitations of angiography, particularly the planar and luminal nature of the imaging, result in incomplete assessment of lesion characteristics which may well contribute to problems with achieving satisfactory outcomes. Intravascular ultrasound (IVUS) is a fundamentally different mode of imaging to angiography and is able to produce high quality imaging of the entire artery rather than just the lumen. IVUS provides a range of imaging parameters, many of which are unique to this form of imaging and are unobtainable with angiography. IVUS can therefore assist with a more complete characterisation of the artery and lesion beyond the luminal silhouette and diameters provided by angiography. In this presentation, the role of intravascular imaging (IVUS) in treating complex femoropopliteal lesions will be reviewed, drawing on more than five years’ experience with this technology. The value of IVUS both before and after treatment will be discussed. This will include how pre-treatment IVUS imaging can assist selection of the most appropriate treatment methods by providing accurate assessment of vessel dimensions, length of the diseased segment, severity of calcification, presence of negative remodelling and the degree of plaque eccentricity. This information can inform the choice of treatment technology as well as optimising device size and the length of treatment. IVUS can also provide unique information after initial treatment. This includes accurate measurement of minimum lumen size post angioplasty and stenting, the presence of dissection and the effects of atherectomy, including assessment of the effectiveness of plaque removal and identification of vessel wall damage. IVUS imaging is simple, quick and safe to use during endovascular interventions and can provide unique information that can supplement standard angiographic imaging and help optimise treatments.

Histological investigation of the effect of Α-Tocopherol on Arterial Wall Structure in Diabetic Rat Model

Cardiovascular diseases are the most important cause of mortality in diabetic individuals. The aim of our study is to investigate histologically whether the use of alpha-tocopherol in diabetic rats would have an effect on the antioxidant system and would provide positive effects on vessel wall damage. For the study, 32 wistar Albino rats were randomly divided into 4 groups. The groups are Control+SF, Control+alpha-tocopherol, DM model, DM+alpha-tocopherol. Arterial tissue specimens were fixed formaldehyde. Routine tissue follow-up was performed and hematoxylin-Eosin (H-E) staining was performed. Arterial wall damage score was calculated. As a result of the evaluation, Kruskal-Wallis, Mann-Whitney U Test and descriptive analyzes were applied for statistical analyzes. In light microscopic examinations; in DM group was determined endothelial cell damage, intracytoplasmic edema and swelling in the smooth muscle cells. In sections of the DM + alpha-tocopherol group, endothelial cells were evaluated as normal. Although there were no differences between DM and DM + alpha-tocopherol groups, there was a significant difference in luminal diameter between Control and DM +alpha-tocopherol in evaluating parameters such as vessel diameter, lumen cap, vessel wall thickness and Tunica media thickness (p˂ 0,005). In our study, the use of alpha-tocopherol in diabetic rats was thought to have an effect on the antioxidant system, which could have a positive effect on vessel wall injury. However, it has come to the conclusion that the therapeutic effect of alpha-tocopherol on cellular damage due to vascular complications in the vascular structure of diabetes is limited.

Vascular Proteomics Reveals Critical Roles of ADAMTS18 in Stroke Associated with Imbalanced Level of Von Willebrand Factor Versus ADAMTS13

Background and Purpose-Stroke is the second leading cause of death worldwide. Acute ischemic stroke (AIS) is frequently induced by internal carotid artery thrombosis. Clinically, most arterial thrombus formation is initiated by platelets adhering to the damaged vessel wall. The adherent platelets become activated and bind with fibrinogen and von Willebrand factor (vWF), allowing formation of a platelet aggregate or mural thrombus. Identifying new mechanism involved in this pathogenesis is critical for understanding the molecular basis of thrombus formation and ultimately developing new therapeutic interventions for stroke. The ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) family comprises 19 secreted metalloproteinases that cleave extracellular matrix components and have diverse functions in numerous disease and physiological contexts. Several ADAMTS genes (ADAMTS -7,-8, 12, and 13) have been shown to be involved in cardiovascular disease and pediatric stroke. ADAMTS18 remains “orphan” protease. We have previously shown that ADAMTS18 deficiency causes abnormal remodeling of the common carotid artery (CCA) and an increase in carotid thrombosis and size of cerebral infarct in mice. Thus, the stroke-prone Adamts18 KO mice could be valuable for identification of molecular signatures of accelerated carotid thrombosis related to stroke. One of the major steps yet to be taken by the field is the widespread use of proteomics to uncover the critical molecular events and signaling pathway involved in ADAMTS gene-related stroke.Methods and Results-Here, we carried out the first proteomics comparison of protein expression patterns in CCA and abdominal artery (AA) between Adamts18 knockout (KO) mice and their wild-type (WT) littermates. A total of 1654 proteins were identified in four separate CCA samples (0.4-1 mg/wet weight each), and 1810 proteins were detected in four separate AA samples (2.3-3.6 mg/wet weight each). The abundances of 154 proteins in CCA and 55 proteins in AA were significantly different between KO and WT mice. Ingenuity® Pathway Analysis revealed that ADAMTS18 deficiency predisposes mice to stroke by altering the abundance of many proteins related to cytoskeleton, prothrombotic activity, coagulation, angiogenesis, oxidative homeostasis, and energy metabolism. Western blotting and qRT-PCR analyses further revealed the imbalanced level of von Willebrand factor and ADAMTS13, the pivotal pathogenic factors of ischemic stroke, in CCA of KO mice.Conclusion and Significance-Results of this first vascular proteomic study of Adamts18 KO mice establish a substantial new resource for investigation of how ADAMTS gene affects cellular phenotypes of stroke. These new findings contribute to inform novel prevention strategies and direct therapeutic development for stroke. DisclosuresNo relevant conflicts of interest to declare.

The association between hypertensive arteriopathy and cerebral amyloid angiopathy in spontaneously hypertensive stroke-prone rats.

We aimed to test the hypothesis that in spontaneously hypertensive stroke‐prone rats (SHRSP), non‐amyloid cerebral small vessel disease/hypertensive arteriopathy (HA) results in vessel wall injury that may promote cerebral amyloid angiopathy (CAA). Our study comprised 21 male SHRSP (age 17–44 weeks) and 10 age‐ and sex‐matched Wistar control rats, that underwent two‐photon (2PM) imaging of the arterioles in the parietal cortex using Methoxy‐X04, Dextran and cerebral blood flow (CBF) measurements. Our data suggest that HA in SHRSP progresses in a temporal and age‐dependent manner, starting from small vessel wall damage (stage 1A), proceeding to CBF reduction (stage 1B), non‐occlusive (stage 2), and finally, occlusive thrombi (stage 3). Wistar animals also demonstrated small vessel wall damage, but were free of any of the later HA stages. Nearly half of all SHRSP additionally displayed vascular Methoxy‐X04 positivity indicative of cortical CAA. Vascular β‐amyloid deposits were found in small vessels characterized by thrombotic occlusions (stage 2 or 3). Post‐mortem analysis of the rat brains confirmed the findings derived from intravital 2PM microscopy. Our data thus overall suggest that advanced HA may play a role in CAA development with the two small vessel disease entities might be related to the same pathological spectrum of the aging brain.

MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis.

Giant cell arteritis (GCA)-a primary vasculitis of medium and large arteries-is associated with vessel wall damage, elastic membrane fragmentation, and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury. The MMP (matrix metalloproteinase)-9-a type IV collagenase-is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent. The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts, and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from patients with GCA. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD (cluster of differentiation) 4+ T cells required MMP-9-producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID (severe combined immunodeficiency) chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting rMMP-9 (recombinant MMP-9). Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates ( P<0.001), reduced intramural neoangiogenesis ( P<0.001), and prevented intimal layer hyperplasia ( P<0.001). rMMP-9 amplified all domains of vasculitic activity, promoted assembly of T-cell infiltrates ( P<0.05), intensified formation of new microvessels ( P<0.001), and worsened intimal thickening ( P<0.001). Systemic delivery of N-acetyl-proline-glycine-proline-a matrikine produced by MMP-9-mediated gelatinolysis-had limited vasculitogenic effects. In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9-producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks, and neointimal growth all require the enzymatic activity of MMP-9, identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis.

Cytokines, Adhesion Molecules, and Matrix Metalloproteases as Predisposing, Diagnostic, and Prognostic Factors in Venous Thrombosis.

The inflammatory response is a well-established part of, and a prerequisite for, venous thrombosis. To better understand the pathophysiology of venous thrombosis and to identify improved diagnostic biomarkers, further studies of the relationship between inflammation and coagulation are needed. We review previous studies concerning inflammatory biomarkers in venous thromboembolism, in particular cytokines, soluble adhesion molecules and matrix metalloproteases as predisposing, diagnostic and prognostic factors in venous thrombosis. Elevated cytokines and genetic alterations coding for cytokines are found in several patient cohorts which indicate that cytokines are involved as predisposing factors in venous thrombosis development. Increased levels of pro-inflammatory cytokines are detected both in animal models and in patients with acute venous thrombosis and clinical trials, although currently without evident diagnostic value. Adhesion molecules are crucial in the development of venous thrombosis, especially P-selectin seems important in initiating leukocyte accumulation and adhesion to endothelium for subsequent platelet accumulation. Several studies have demonstrated increased soluble P-selectin levels in patients with venous thrombosis, emphasizing its potential role as diagnostic marker and also as a therapeutic target. Matrix metalloproteases are essential effectors during venous thrombosis resolution and may impact vessel wall fibrosis, and together with their natural occurring inhibitors are crucial in acute and chronic thrombosis pathophysiology. Furthermore, studies in animal models of venous thrombosis have demonstrated anti-inflammatory treatment to be effective in terms of thrombus resolution and reduction of vessel wall damage, without increase in bleeding risk during the course of treatment. Thus, soluble mediators should be further investigated both as possible biomarkers and therapeutic targets in venous thromboembolic disease.

Numerical Solution for Blood Losses Phenomenon in Narrow Vessels

Some diseases have blood losses as one of their clinical characteristics. The bleeding patient could die if it is no properly and quickly handled. In this paper, it is constructed a mathematical model to study the velocity and the pressure in the body during blood losses through the vessel wall. Furthermore, the effects of blood losses to the velocity and pressure during the bleeding are shown here. In this work, the blood flow is modeled using Stokes equation, while the blood leaks are captured using Darcy's law as a boundary condition. Darcy's law is used because a damaged vessel wall can be depicted as a porous material. A numerical approach in two-dimensional using the Finite Different Method is used in this paper. Numerical results show a significant decreasing of the mean velocity and the mean pressure in the vessels due to the blood losses.

Mechanism of action of the vascular disrupting agent OXi8006 on activated endothelial cell signaling

Tumor cell survival, growth, and metastasis require a functioning vascular network to provide oxygen and nutrient supply. While the endothelium of normal, remodeled blood vessels is largely quiescent, the neovasculature of tumors is immature, less differentiated, distinct in morphology, lacking in pericyte support, more responsive to angiogenic cell signaling, and exhibits increased permeability. Consequently, tumor vasculature offers a unique, potentially selective target for anticancer therapy. The goal of treatment with vascular disrupting agents (VDAs) is to instigate rapid, widespread disruption of existing tumor vasculature, leading to blood flow shutdown, followed by induction of microenvironmental hypoxia and profound tumor necrosis. This mechanism is dissimilar from that of angiogenesis inhibiting agents (AIAs), which prevent the growth of new blood vessels. Not all VDAs are inhibitors of tubulin polymerization, but most promising pre‐clinical VDA candidates function by interfering with microtubule dynamics through binding to the colchicine site on the tubulin heterodimer in endothelial cells lining tumor‐associated vasculature. This interaction causes rapid morphological changes, which results in increased vessel permeability, cell detachment, irreversible vessel occlusion and wall damage. Understanding the signaling mechanism of drug action at the molecular level is essential for predicting potential off target effects, and providing information to circumvent drug resistance. Previously, we have demonstrated that treatment with the VDA OXi8006 in activated human umbilical vein endothelial cells (HUVECs), a model for tumor vessel endothelium, resulted in profound restructuring of cytoskeletal networks, indicated by microtubule collapse followed closely by focal adhesion‐anchored actin stress fiber formation and correlated to an increase in phosphorylation of myosin light chain, focal adhesion kinase, and the filamentous actin severing protein, cofilin. Cytoskeletal crosstalk subsequent to vascular disruption, was modulated by the intramolecular switch, RhoA, and its downstream effector RhoA kinase (ROCK). In the present study, we have investigated the connection between microtubule catastrophe and activation of the GTP‐ase RhoA. Two guanine nucleotide exchange factors (GEFs) that associate with microtubules, GEF‐H1 and p190RhoGEF (RGNEF) were independently knocked down (KD) by siRNA in HUVECs, confirmed by western blotting and confocal microscopy. OXi8006 treatment of GEF‐H1 KD HUVECs resulted in microtubule collapse, yet downstream events associated with VDA treatment were abrogated or greatly diminished. Contrastingly, OXi8006 mediated collapse of microtubules in p190RhoGEF KD HUVECs was followed by actin stress fiber formation and an increase in phosphorylation of myosin light chain, focal adhesion kinase, and cofilin, similar to responses observed in control HUVECs. Our data confirm the role of GEF‐H1, but not p190RhoGEF in mediating activation of RhoA in OXi8006 treated endothelial cells.Support or Funding InformationCPRIT RP140399, National Institutes of Health National Cancer Institute 5R01CA140674This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Flow-induced adhesion of shear-activated polymers to a substrate

Adhesion of polymers and proteins to substrates plays a crucial role in many technological applications and biological processes. A prominent example is the von Willebrand factor (VWF) protein, which is essential in blood clotting as it mediates adhesion of blood platelets to the site of injury at high shear rates. VWF is activated by flow and is able to bind efficiently to damaged vessel walls even under extreme flow-stress conditions; however, its adhesion is reversible when the flow strength is significantly reduced or the flow is ceased. Motivated by the properties and behavior of VWF in flow, we investigate adhesion of shear-activated polymers to a planar wall in flow and whether the adhesion is reversible under flow stasis. The main ingredients of the polymer model are cohesive inter-monomer interactions, a catch bond with the adhesive surface, and the shear activation/deactivation of polymer adhesion correlated with its stretching in flow. The cohesive interactions within the polymer maintain a globular conformation under low shear stresses and allow polymer stretching if a critical shear rate is exceeded, which is directly associated with its activation for adhesion. Our results show that polymer adhesion at high shear rates is significantly stabilized by catch bonds, while at the same time they also permit polymer dissociation from a surface at low or no flow stresses. In addition, the activation/deactivation mechanism for adhesion plays a crucial role in the reversibility of its adhesion. These observations help us better understand the adhesive behavior of VWF in flow and interpret its adhesion malfunctioning in VWF-related diseases.

Bioinformatic analysis of gene expression profiling of intracranial aneurysm.

Intracranial aneurysm (IA) is a severe clinical condition of primary concern and currently, there is no effective therapeutic reagent. The present study aimed to investigate the molecular mechanism of IA via bioinformatic analysis. Various gene expression profiles (GSE26969) were downloaded from the Gene Expression Omnibus database, including 3 IA and 3 normal superficial temporal artery samples. Firstly, the limma package in R language was used to identify differentially expressed genes (DEGs; P-value <0.01 and |log2 FC|≥1). Secondly, the database for annotation, visualization and integrated discovery software was utilized to perform pathway and functional enrichment analyses (false discovery rate ≤0.05). Finally, protein-protein interaction (PPI) network and sub-network clustering analyses were performed using the biomolecular interaction network database and ClusterONE software, respectively. Following this, a transcription factor regulatory network was identified from the PPI network. A total of 1,124 DEGs were identified, of which 989 were upregulated and 135 downregulated. Pathway and functional enrichment analyses revealed that the DEGs primarily participated in RNA splicing, functioning of the spliceosome, RNA processing and the mRNA metabolic process. Following PPI network analysis, 1 hepatocyte nuclear factor (HNF) 4A (transcription factor)-centered regulatory network and 5 DEG-centered sub-networks were identified. On analysis of the transcription factor regulatory network, 6 transcription factors (HNF6, HNF4A, E2F4, YY1, H4 and H31T) and a regulatory pathway (HNF6-HNF4-E2F4) were identified. The results of the present study suggest that activating transcription factor-5, Jun proto-oncogene, activator protein-1 transcription factor subunit, HNF6, HNF4 and E2F4 may participate in IA progression via vascular smooth muscle cell apoptosis, inflammation, vessel wall remodeling and damage and the tumor necrosis factor-β signaling pathway. However, further experimental studies are required to validate these predictions.

Fibroblast growth factor 21 ameliorates vascular calcification by inhibiting osteogenic transition in vitamin D3 plus nicotine-treated rats

FGF21, a special member of FGF superfamily, has been proven to have pleiotropic metabolic effects and many potential therapeutic action in various metabolic disorders. Vascular calcification (VC), a perplexing clinical issue, is a major risk factor for many cardiovascular diseases, especially for patients with some metabolic diseases. However, the role of FGF21 on VC in vivo remains unclear. Thus, in this study, we observed the effect and mechanism of FGF21 on VC induced by vitamin D3 plus nicotine (VDN) treated rats. After four weeks' treatment, the calcium overload is mainly manifested in the increased blood pressure, aortic calcium content and ALP activity. Also, the HE and Alizarin-red S staining showed the structural damage of calcified vessel walls. In addition, the level of endogenous FGF21/β-Klotho/FGFR1 axis was up-regulated in the aortas of VC rats. Furthermore, exogenous FGF21 treatment significantly ameliorated the aortic injury and calcification in VC rats, and the level of β-Klotho and FGFR1 were furtherly increase. Moreover, FGF21 inhibited the osteogenic transition of VSMCs by down-regulating the expression of bone-associated proteins such as osteopontin (OPN), osteocalcin (OCN) and bone morphogenetic protein-2 (BMP-2), together with restored the expression of SM22α and SM α-actin, which are two of lineage markers in VSMCs. We provide the first evidence that FGF21 can inhibit the development of VC by inhibiting the osteogenic transition of VSMCs in rats. FGF21 might be an efficient endogenous vasoprotective factor for calcification.

Entrapment of Autologous von Willebrand Factor on Polystyrene/Poly(methyl methacrylate) Demixed Surfaces.

Human platelets play a vital role in haemostasis, pathological bleeding and thrombosis. The haemostatic mechanism is concerned with the control of bleeding from injured blood vessels, whereby platelets interact with the damaged inner vessel wall to form a clot (thrombus) at the site of injury. This adhesion of platelets and their subsequent aggregation is dependent on the presence of the blood protein von Willebrand Factor (vWF). It is proposed here that the entrapment of vWF on a substrate surface offers the opportunity to assess an individual’s platelet function in a clinical diagnostic context. Spin coating from demixed solutions of polystyrene (PS) and poly(methyl methacrylate) (PMMA) onto glass slides has been shown previously to support platelet adhesion but the mechanism by which this interaction occurs, including the role of vWF, is not fully understood. In this work, we report a study of the interaction of platelets in whole blood with surfaces produced by spin coating from a solution of a weight/weight mixture of a 25% PS and 75% PMMA (25PS/75PMMA) in chloroform in the context of the properties required for their use as a Dynamic Platelet Function Assay (DPFA) substrate. Atomic Force Microscopy (AFM) indicates the presence of topographical features on the polymer demixed surfaces in the sub-micron to nanometer range. X-ray Photoelectron Spectroscopy (XPS) analysis confirms that the uppermost surface chemistry of the coatings is solely that of PMMA. The deliberate addition of various amounts of 50 μm diameter PS microspheres to the 25PS/75PMMA system has been shown to maintain the PMMA chemistry, but to significantly change the surface topography and to subsequently effect the scale of the resultant platelet interactions. By blocking specific platelet binding sites, it has been shown that their interaction with these surfaces is a consequence of the entrapment and build-up of vWF from the same whole blood sample.

Clots Are Potent Triggers of Inflammatory Cell Gene Expression

Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine whether clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases. We performed next-generation RNA sequencing on monocytes extracted from whole blood clots and using a purified plasma clot system. Numerous mRNAs were differentially expressed by monocytes embedded in clots compared with unclotted controls, and IL-8 (interleukin 8) and MCP-1 (monocyte chemoattractant protein-1) were among the upregulated transcripts in both models. Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in lipopolysaccharide-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (ie, 1-2 hours) reduced the synthesis of IL-8 and MCP-1, whereas delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1. These findings demonstrate that clots are potent inducers of monocyte gene expression and that timely fibrinolysis attenuates inflammatory responses, specifically IL-8 and MCP-1. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically proven efficacy of fibrinolytic drug treatment within hours of stroke onset.

Clinicopathological analysis of nine cases of dermatomyositis with panniculitis as a skin manifestation

Objective To analyze clinical and pathological features of dermatomyositis with pan-niculitis as a skin manifestation. Methods Clinical data were collected from 9 cases of dermatomyositis with panniculitis as a skin manifestation in Department of Dermatology of Zhongshan Hospital affiliated to Fudan University from October 2012 to July 2016, and their clinical and pathological features were analyzed. Results Of the 9 cases, 6 were female and 3 were male, and the age ranged from 28 to 73 years. Panniculitis lesions of the 9 patients all manifested as painful indurated plaques or nodules on the buttock, thigh, waist, back, abdomen, upper extremities and cheeks. These lesions occurred before, after or simultaneously with the onset of characteristic skin and muscle lesions of dermatomyositis, especially preceded the onset of characteristic lesions of dermatomyositis by 30 years in 1 case. Histopathological examination of lesions showed liquefaction degeneration of basal cells, inflammatory infiltration of lymphocytes and plasma cells around blood vessels, in the fat lobules as well as between the lobules and septa in the dermis. The necrosis and calcification of lipocytes, lipomembranous changes, fibrinoid necrosis of damaged vessel walls and microvascular occlusion were observed in some cases. Because panniculitis preceded the onset of characteristic lesions of dermatomyositis, 2 patients were misdiagnosed with lupus panniculitis and morphea profunda for several times. Most patients had good response to systemic glucocorticoids combined with immunosuppressive agents, while the patients with lipomembranous fat necrosis had poor response to the combination therapy. Conclusions Panniculitis lesions of dermatomyositis are histologically characteristic, and may do not coincide with the onset of characteristic lesions of dermatomyositis. If panniculitis lesions precede characteristic lesions of dermatomyositis, patients will be easily misdiagnosed. Thus, persistent follow-up visit will be of great importance for the diagnosis. Key words: Dermatomyositis; Panniculitis; Antibodies, antinuclear; Glucocorticoids; Immuno-suppressive agents