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Showing 841–860 of 2058 publications.
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Hawkins, Clare L.; Rayner, Benjamin SaulHypobromous acid (HOBr) and hypothiocyanous acid (HOSCN) are produced by a number of human peroxidase enzymes, including myeloperoxidase (MPO), eosinophil peroxidase (EPO), and lactoperoxidase (LPO), via the reaction of hydrogen peroxide with bromide (Br?) and thiocyanate (SCN?) ions, respectively [1-6]. HOBr and HOSCN are chemical oxidants that react with biological molecules and cells with quite different potency and selectivity [1,7]. In each case, these oxidants are critical in immune defense, as each has powerful antibacterial, antiviral, and antifungal properties (e.g., [8-13]). However, in some cases, the overproduction of these oxidants during chronic inflammation has been implicated in the development of disease [12,13]. For example, HOBr is believed to contribute to tissue damage in the lungs of patients with asthma, shown by the detection of elevated amounts of the biomarker 3-bromo-Tyr [12,14]. In contrast to HOBr, which is generally regarded as a damaging oxidant, the role of HOSCN in disease is unclear. Thus, some studies provide evidence to support cellular damage on exposure to this oxidant, which may exacerbate disease (reviewed [7,13]), while others support a potentially protective role of elevated SCN? in inflammatory disease (reviewed [15,16]). 328This chapter will review the formation and reactivity of HOBr and HOSCN in biological systems, and discuss the implications of these reactions in both immune defense and disease. 2018 by Taylor & Francis Group, LLC.
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Callaghan, Fraser Maurice; Arnott, Clare; Figtree, Gemma A.; Kutty, Shelby; Celermajer, David S.; Grieve, Stuart M.Purpose: To quantitatively characterize the central role of vortex formation on the flow patterns and energy transfer within the right atrium (RA). Materials and Methods: 4D-flow magnetic resonance imaging (MRI) data with multiple encoding velocities was acquired in 12 healthy subjects at 3T. Particles entering the RA were classified according to the origin of entry. Vortex membership was numerically derived by assessing the location of pathline center of curvature relative to the vortex core, defined by Q-criteria. Flow dynamics and energetics were assessed using paired t-tests. Results: The majority of flow (74%) passes through the RA in a single beat, with a very small volume fraction retained longer than two beats (<1%). RA flow was dominated by a governing vortex, comprising 79% of total flow, and acting to preserve kinetic energy. Flow comprising the vortex enters the RA significantly earlier than nonvortex flow (P < 0.01). The majority of nonvortex flow enters the RA during systole, traversing the RA via a direct path with a significantly shorter residence time and distance traveled (both P < 0.01). Conclusion: Blood flow momentum is preserved during systole within a dominant vortex, which we are able to characterize numerically using a semiautomated approach. Our analytical approach has potential for application to understanding right heart function in health and disease. Level of Evidence: 1. J. Magn. Reson. Imaging 2017;45:10461054. 2016 International Society for Magnetic Resonance in Medicine
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Santos, Miguel; Waterhouse, Anna; Lee, Bob S.L.; Chan, Alex H.P.; Tan, Richard P.; Michael, Praveesuda Lorwattanapongsa; Filipe, Elysse C.; Hung, Juichien; Wise, Steven G.; Bilek, Marcela M.M.This chapter describes a simple measure to address issues in the use of stents, that is, the inherent thrombogenicity of metallic implants, destruction of the protective endothelial cell layer lining arterial walls, chronic inflammation, and the renarrowing of the treated artery (restenosis). Unfortunately, the drugs (taxus and limus family) eluted from drug-eluting stents (DES) to halt restenosis cause endothelial dysfunction and hypersensitivity, contributing to thrombogenic potential. The deposition of biofunctional thin-film coatings, suitable for coronary stents, has been previously demonstrated using plasma-activated coatings (PAC) on various substrates. PAC was designed to overcome many of the thrombogenic properties of metal and DES drugs. Modified tropoelastin, fibronectin, plasmin, and streptokinase, all bound to the stent surface by PAC, have showed promise, as tropoelastin is the major regulator of smooth muscle cell proliferation in vivo, fibronectin encourages endothelial cell regeneration, and plasmin and streptokinase have thrombolytic properties. 2018 Elsevier Ltd. All rights reserved.
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Lam, Yuenting; Lecce, Laura; Bursill, C. A.; Ng, Martin K.C.Sex steroids such as estrogen and testosterone are key mediators of angiogenesis. They are implicated in both physiological and pathological angiogenesis such as during the menstrual cycle, wound healing and cancer growth and progression. Sex steroids regulate many aspects of angiogenesis through both classic genomic transcription modulation and rapid non-genomic signaling pathways. In this capacity, sex steroids modulate endothelial and progenitor cell functions such as proliferation, migration and attachment, which are all essential components involved in neovascularization. Since sex steroids are known to augment angiogenesis which is vital to tumor progression and growth, common treatment of hormone responsive tumors is through sex steroid receptor antagonists or hormone deprivation. Due to the involvement of sex steroids in necessary physiological functions as well as the potential to promote pathological angiogenesis, it is fundamental that the mechanisms behind sex steroid-mediated neovascularization are understood. Springer International Publishing AG 2017.
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Charlton, Francesca; Bobek, Gabriele; Stait-Gardner, Timothy; Price, William S.; Colafella, Katrina Mirabito; Xu, Bei; Makris, Angela; Rye, Kerry Anne; Hennessy, AnnemariePreeclampsia is a hypertensive disorder of pregnancy. It is associated with abnormal placentation via poor placental invasion of the uterine vasculature by trophoblast cells, leading to poor placental perfusion, oxidative stress, and inflammation, all of which are implicated in its pathogenesis. A dyslipidemia characterized by low plasma levels of high-density lipoproteins (HDL) and elevated triglycerides has been described in preeclampsia. Apolipoprotein A-I (apoA-I), a constituent of HDL is an antiinflammatory agent. This study investigated whether apoA-I protects against hypertension and adverse placental changes in a proinflammatory cytokine (TNF-?)-induced model of preeclampsia. Further, this study investigated whether apoA-I protects against the inhibitory effect of TNF-? in a human in vitro model of trophoblast invasion. Administration of apoA-I to pregnant mice before infusion with TNF-? resulted in a significant reduction in the cytokine-induced increase in systolic blood pressure. MRI measurement of T2 relaxation, a parameter that is tissue specific and sensitive to physiological changes within tissues, showed a reversal of TNF-?-induced placental changes. Preincubation of endothelial cells with apoA-I protected against the TNF-?-induced inhibition of HTR-8/SVneo (trophoblast) cell integration into endothelial (UtMVEC) networks. These data suggest that a healthy lipid profile may affect pregnancy outcomes by priming endothelial cells in preparation for trophoblast invasion. 2017 the American Physiological Society.
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Ju, Lining Arnold; Chen, Yunfeng; Rushdi, Muaz Nik; Chen, Wei; Zhu, ChengUpon engagement with a specific ligand, a cell surface receptor transduces intracellular signals to activate various cellular functions. This chapter describes a set of biomechanical methods for analyzing the characteristics of cross-junctional receptorligand interactions at the surface of living cells. These methods combine the characterization of kinetics of receptorligand binding with real-time imaging of intracellular calcium fluxes, which allow researchers to assess how the signal initiated from single receptorligand engagement is transduced across the cell membrane. A major application of these methods is the analysis of antigen recognition by triggering of the T cell receptor (TCR). Three related methods are described in this chapter: (1) the micropipette adhesion assay, (2) the biomembrane force probe (BFP) assay, and (3) combining BFP with fluorescence microscopy (fBFP). In all cases, an ultrasoft human red blood cell (RBC) is used as an ultrasensitive mechanical force probe. The micropipette assay detects binding events visually. The BFP uses a high-speed camera and real-time image tracking techniques to measure mechanical variables on a single molecular bond with up to ~1 pN (10?12 Newton), ~3 nm (10?9 m), and ~0.5 ms (10?3 s) in force, spatial, and temporal resolution, respectively. As an upgrade to the BFP, the fBFP simultaneously images binding-triggered intracellular calcium signals on a single live cell. These technologies can be widely used to study other membrane receptorligand interactions and signaling under mechanical regulation. Springer Science+Business Media LLC 2017.
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Pathmarajah, Tishanthan; Abdelhamid, M.; Tenna, Adriano Sala; Paton, David J.W.; Hockley, Joseph Allan; Jansen, Shirley JaneIntroduction Endovascular aneurysm repair (EVAR) is the most commonly used approach for treatment of abdominal aortic aneurysms (AAA). Testicular infarction is a rare complication of EVAR. A novel case of acute global testicular infarction post-EVAR from cholesterol embolisation mimicking torsion is presented. Report A 75 year old man developed acute right testicular ischaemia requiring orchidectomy following EVAR of an infrarenal aortic aneurysm. The patient was initially diagnosed with testicular torsion as the aetiology of the infarction; however, on re-analysis of histopathology it was found to be secondary to cholesterol emboli. Discussion In patients complaining of groin/scrotal pain following EVAR, it is worth considering testicular ischaemia whether secondary to cholesterol embolisation or gonadal occlusion. Clinicians should be aware that clinical and radiological findings can mimic torsion as this affects management and outcome. 2017 The Authors
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Lip, Gregory Y.H.; Freedman, Ben Ben; De Caterina, Raffaele; Potpara, Tatjana S.Concepts and our approaches to stroke prevention in atrial fibrillation (AF) have changed markedly over the last decade. There has been an evolution over the approach to stroke and bleeding risk assessment, as well as new treatment options. An increasing awareness of AF has led to calls to improve the detection of and population screening for AF. Stroke and bleeding risk assessment continues to evolve, and the ongoing debate on balance between simplicity and practicality, against precision medicine will continue. In this review article, we provide an overview of past, present and the (likely) future concepts and approaches to stroke prevention in AF. We propose three simple steps (the Birmingham 3-step) that offers a practical management pathway to help streamline and simplify decision-making for stroke prevention in patients with AF. Schattauer 2017.
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Indo, Hiroko P.; Hawkins, Clare L.; Nakanishi, Ikuo; Matsumoto, Kenichiro; Matsui, Hirofumi; Suenaga, Shigeaki; Davies, Michael J.; St. Clair, Daret K.; Ozawa, Tosfiihiko; Majima, Hideyuki J.Mitochondria are a major source of intracellular energy and reactive oxygen species in cells, but are also increasingly being recognized as a controller of cell death. Here, we review evidence of signal transduction control by mitochondrial superoxide generation via the nuclear factor-?B (NF-?B) and GATA signaling pathways. We have also reviewed the effects of ROS on the activation of MMP and HIF. There is significant evidence to support the hypothesis that mitochondrial superoxide can initiate signaling pathways following transport into the cytosol. In this study, we provide evidence of TATA signal transductions by mitochondrial superoxide. Oxidative phosphorylation via the electron transfer chain, glycolysis, and generation of superoxide from mitochondria could be important factors in regulating signal transduction, cellular homeostasis, and cell death. Springer International Publishing Switzerland 2016.
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Wachter, Rolf; Freedman, Ben Ben[No abstract available]
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van der Vorst, Emiel P.C.; Theodorou, Kosta; Wu, Yongzheng; Hoeksema, Marten Anne; Goossens, Pieter G.; Bursill, C. A.; Aliyev, Taghi; Huitema, Leonie F.A.; Tas, Sander W.; Wolfs, Ine M.J.; Kuijpers, Marijke J.E.; Gijbels, Marion J.J.; Schalkwijk, Casper G.; Koonen, Debby P.Y.; Abdollahi-Roodsaz, Shahla; McDaniels, Kimberly R.; Wang, Chihchieh; Leitges, M.; Lawrence, Toby J.; Plat, Jogchum; van Eck, Miranda; Rye, Kerry Anne; Touqui, Lhousseine; de Winther, Menno P.J.; Biessen, Erik A.L.; Donners, Marjo M.P.C.Membrane cholesterol modulates a variety of cell signaling pathways and functions. While cholesterol depletion by high-density lipoproteins (HDLs) has potent anti-inflammatory effects in various cell types, its effects on inflammatory responses in macrophages remain elusive. Here we show overt pro-inflammatory effects of HDL-mediated passive cholesterol depletion and lipid raft disruption in murine and human primary macrophages invitro. These pro-inflammatory effects were confirmed invivo in peritoneal macrophages from apoA-I transgenic mice, which have elevated HDL levels. In line withthese findings, the innate immune responses required for clearance of P.aeruginosa bacterial infection in lung were compromised in mice with low HDL levels. Expression analysis, ChIP-PCR, and combinatorial pharmacological and genetic intervention studies unveiled that both native and reconstituted HDL enhance Toll-like-receptor-induced signaling by activating a PKC-NF-?B/STAT1-IRF1 axis, leading to increased inflammatory cytokine expression. HDL's pro-inflammatory activity supports proper functioning of macrophage immune responses. 2017 Elsevier Inc.
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Lok, Hiu Chuen; Sahni, Sumit; Jansson, Patric J.; Kova?evi?, aklina; Hawkins, Clare L.; Richardson, Des RaymondNitric oxide (NO) is integral to macrophage cytotoxicity against tumors due to its ability to induce iron release from cancer cells. However, the mechanism for how activated macrophages protect themselves from endogenous NO remains unknown. We previously demonstrated by using tumor cells that glutathione S-transferase P1 (GSTP1) sequesters NO as dinitrosyl-dithiol iron complexes (DNICs) and inhibits NO-mediated iron release from cells via the transporter multidrug resistance protein 1 (MRP1/ABCC1). These prior studies also showed that MRP1 and GSTP1 protect tumor cells against NO cytotoxicity, which parallels their roles in defending cancer cells from cytotoxic drugs. Considering this, and because GSTP1 and MRP1 are up-regulated during macrophage activation, this investigation examined whether this NO storage/transport system protects macrophages against endogenous NO cytotoxicity in two well characterized macrophage cell types (J774 and RAW 264.7). MRP1 expression markedly increased upon macrophage activation, and the role of MRP1 in NO-induced 59Fe release was demonstrated by Mrp1 siRNA and the MRP1 inhibitor, MK571, which inhibited NO-mediated iron efflux. Furthermore, Mrp1 silencing increased DNIC accumulation in macrophages, indicating a role for MRP1 in transporting DNICs out of cells. In addition, macrophage 59Fe release was enhanced by silencing Gstp1, suggesting GSTP1 was responsible for DNIC binding/storage. Viability studies demonstrated that GSTP1 and MRP1 protect activated macrophages from NO cytotoxicity. This was confirmed by silencing nuclear factor-erythroid 2-related factor 2 (Nrf2), which decreased MRP1 and GSTP1 expression, concomitant with reduced 59Fe release and macrophage survival. Together, these results demonstrate a mechanism by which macrophages protect themselves against NO cytotoxicity. 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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Indo, Hiroko P.; Majima, Hideyuki J.; Terada, Masahiro; Suenaga, Shigeaki; Tomita, Kazuo; Yamada, Shin; Higashibata, Akira; Ishioka, Noriaki; Kanekura, Takuro; Nonaka, Ikuya; Hawkins, Clare L.; Davies, Michael J.; St. Clair, Daret K.; Mukai, Chiaki N.The effects of long-term exposure to extreme space conditions on astronauts were investigated by analyzing hair samples from ten astronauts who had spent six months on the International Space Station (ISS). Two samples were collected before, during and after their stays in the ISS; hereafter, referred to as Preflight, Inflight and Postflight, respectively. The ratios of mitochondrial (mt) to nuclear (n) DNA and mtRNA to nRNA were analyzed via quantitative PCR. The combined data of Preflight, Inflight and Postflight show a significant reduction in the mtDNA/nDNA in Inflight, and significant reductions in the mtRNA/nRNA ratios in both the Inflight and Postflight samples. The mtRNA/mtDNA ratios were relatively constant, except in the Postflight samples. Using the same samples, the expression of redox and signal transduction related genes, MnSOD, CuZnSOD, Nrf2, Keap1, GPx4 and Catalase was also examined. The results of the combined data from Preflight, Inflight and Postflight show a significant decrease in the expression of all of the redox-related genes in the samples collected Postflight, with the exception of Catalase, which show no change. This decreased expression may contribute to increased oxidative stress Inflight resulting in the mitochondrial damage that is apparent Postflight. 2016, The Author(s).
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Evin, Morgane A.; Broadhouse, Kathryn M.; Callaghan, Fraser Maurice; McGrath, Rachel T.; Glastras, Sarah J.; Kozor, Rebecca A.; Hocking, Samantha L.; Lamy, Je; Redheuil, Alban B.; Kachenoura, N.; Fulcher, Greg R.; Figtree, Gemma A.; Grieve, Stuart M.Background: Diastolic dysfunction is a major cause of morbidity in obese individuals. We aimed to assess the ability of magnetic resonance imaging (MRI) derived left atrial (LA) strain to detect early diastolic dysfunction in individuals with obesity and type 2 diabetes, and to explore the association between cardiac adipose tissue and LA function. Methods: Twenty patients with obesity and T2D (55 8 years) and nineteen healthy controls (48 13 years) were imaged using cine steady state free precession and 2-point Dixon cardiovascular magnetic resonance. LA function was quantified using a feature tracking technique with definition of phasic longitudinal strain and strain rates, as well as radial motion fraction and radial velocities. Results: Systolic left ventricular size and function were similar between the obesity and type 2 diabetes and control groups by MRI. All patients except four had normal diastolic assessment by echocardiography. In contrast, measures of LA function using magnetic resonance feature tracking were uniformly altered in the obesity and type 2 diabetes group only. Although there was no significant difference in intra-myocardial fat fraction, Dixon 3D epicardial fat volume(EFV) was significantly elevated in the obesity and type 2 diabetes versus control group (135 31 vs. 90 30 mL/m2, p < 0.001). There were significant correlations between LA functional indices and both BMI and EFV (p ? 0.007). Conclusions: LA MRI-strain may be a sensitive tool for the detection of early diastolic dysfunction in individuals with obesity and type 2 diabetes and correlated with BMI and epicardial fat supporting a possible association between adiposity and LA strain. Trials Registration Australian New Zealand Clinical Trials Registry No. ACTRN12613001069741 2016 The Author(s).
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Karimi, Maryam; Ignasiak, Marta Teresa; Chan, Bun; Croft, Anna K.; Radom, Leo; Schiesser, Cart H.; Pattison, David I.; Davies, Michael J.Disulfide bonds play a key role in stabilizing protein structures, with disruption strongly associated with loss of protein function and activity. Previous data have suggested that disulfides show only modest reactivity with oxidants. In the current study, we report kinetic data indicating that selected disulfides react extremely rapidly, with a variation of 104 in rate constants. Five-membered ring disulfides are particularly reactive compared with acyclic (linear) disulfides or six-membered rings. Particular disulfides in proteins also show enhanced reactivity. This variation occurs with multiple oxidants and is shown to arise from favorable electrostatic stabilization of the incipient positive charge on the sulfur reaction center by remote groups, or by the neighboring sulfur for conformations in which the orbitals are suitably aligned. Controlling these factors should allow the design of efficient scavengers and high-stability proteins. These data are consistent with selective oxidative damage to particular disulfides, including those in some proteins. 2016 The Author(s).
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Cartland, Si; Genner, Scott W.; Zahoor, Amna; Kavurma, Mary M.Tumor necrosis-factor-related apoptosis-inducing ligand (TRAIL) has been implicated in angiogenesis, the growth of new blood vessels from an existing vessel bed. Our aim was to compare pro-angiogenic responses of TRAIL, vascular endothelial growth-factor-A (VEGF-A) and fibroblast growth-factor-2 (FGF-2) either separately (10 ng/mL) or in combination, followed by the assessment of proliferation, migration and tubule formation using human microvascular endothelial-1 (HMEC-1) cells in vitro. Angiogenesis was also measured in vivo using the Matrigel plug assay. TRAIL and FGF-2 significantly augmented HMEC-1 cell proliferation and migration, with combination treatment having an enhanced effect on cell migration only. In contrast, VEGF-A did not stimulate HMEC-1 migration at 10 ng/mL. Tubule formation was induced by all three factors, with TRAIL more effective compared to VEGF-A, but not FGF-2. TRAIL at 400 ng/mL, but not VEGF-A, promoted CD31-positive staining into the Matrigel plug. However, FGF-2 was superior, stimulating cell infiltration and angiogenesis better than TRAIL and VEGF-A in vivo. These findings demonstrate that each growth factor is more effective at different processes of angiogenesis in vitro and in vivo. Understanding how these molecules stimulate different processes relating to angiogenesis may help identify new strategies and treatments aimed at inhibiting or promoting dysregulated angiogenesis in people. 2016 by the authors; licensee MDPI, Basel, Switzerland.
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Freedman, Ben Ben[No abstract available]
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Ismael, Fahd O.; Barrett, Tessa J.; Sheipouri, Diba; Brown, Bronwyn E.; Davies, Michael J.; Hawkins, Clare L.Low-density lipoprotein (LDL) is the major source of lipid within atherosclerotic lesions. Myeloperoxidase (MPO) is present in lesions and forms the reactive oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). These oxidants modify LDL and have been strongly linked with the development of atherosclerosis. In this study, we examined the effect of HOCl, HOSCN and LDL pre-treated with these oxidants on the function of lysosomal enzymes responsible for protein catabolism and lipid hydrolysis in murine macrophage- like J774A.1 cells. In each case, the cells were exposed to HOCl or HOSCN or LDL pre-treated with these oxidants. Lysosomal cathepsin (B, L and D) and acid lipase activities were quantified, with cathepsin and LAMP-1 protein levels determined by Western blotting. Exposure of J774A.1 cells to HOCl or HOSCN resulted in a significant decrease in the activity of the Cys-dependent cathepsins B and L, but not the Asp-dependent cathepsin D. Cathepsins B and L were also inhibited in macrophages exposed to HOSCN-modified, and to a lesser extent, HOCl-modified LDL. No change was seen in cathepsin D activity or the expression of the cathepsin proteins or lysosomal marker protein LAMP-1. The activity of lysosomal acid lipase was also decreased on treatment of macrophages with each modified LDL. Taken together, these results suggest that HOCl, HOSCN and LDL modified by these oxidants could contribute to lysosomal dysfunction and thus perturb the cellular processing of LDL, which could be important during the development of atherosclerosis. 2016 Ismael et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Larsson, Pia; Alwis, Imala D.; Niego, Be'Eri; Sashindranath, Maithili; Fogelstrand, Per; Wu, Mike C.L.; Glise, Lars; Magnusson, Mia; Daglas, Maria; Bergh, Niklas; Jackson, Shaun P.; Medcalf, Robert Lindsay; Jern, Sverker C.Essentials Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. Valproic acid increased tissue plasminogen activator expression in vascular endothelium. Valproic acid reduced fibrin deposition and thrombus formation after vascular injury. Summary: Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo. 2016 International Society on Thrombosis and Haemostasis
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Lam, Yuen Ting; Lecce, Laura; Tan, Joanne Tsui Ming; Bursill, C. A.; Handelsman, David J.; Ng, Martin K.C.Increasing evidence indicates that androgens regulate ischemia-induced neovascularization. However, the role of genomic androgen action mediated by androgen receptor (AR), a ligand-activated nuclear transcription factor, remains poorly understood. Using an AR knockout (KO) mouse strain that contains a transcriptionally inactive AR (AR?ex3KO), we examined the role of AR genomic function in modulating androgen-mediated augmentation of ischemia-induced neovascularization. Castrated wild-type (ARWT) and AR?ex3KO mice were implanted with 5?-dihydrotestosterone (DHT) or placebo pellets after hindlimb ischemia (HLI). DHT modulation of angiogenesis and vasculogenesis, key processes for vascular repair and regeneration, was examined. Laser Doppler perfusion imaging revealed thatDHTenhanced blood flow recovery inARWTmice post-HLI. InARWT mice, DHT enhanced angiogenesis by down-regulating prolyl hydroxylase 2 and augmenting hypoxia-inducible factor-1? (HIF-1?) levels in the ischemic tissues post-HLI. DHT also enhanced the production and mobilization of Sca1?/CXCR4? progenitor cells in the bone marrow (BM) and circulating blood, respectively, in ARWT mice. By contrast, DHT-mediated enhancement of blood flow recovery was abrogated in AR?ex3KO mice. DHT modulation of HIF-1? expression was attenuated in AR?ex3KO mice. DHT-induced HIF-1? transcriptional activity and DHT-augmented paracrine-mediated endothelial cell tubule formation were attenuated in fibroblasts isolated from AR?ex3KO mice in vitro. Furthermore, DHT-induced augmentation of Sca1?/CXCR4? progenitor cell production and mobilization was absent in AR?ex3KO mice post-HLI. BM transplantation revealed that ischemia-induced mobilization of circulating progenitor cells was abolished in recipients of AR?ex3KO BM. Together, these results indicate that androgen-mediated augmentation of ischemia-induced neovascularization is dependent on genomic AR transcriptional activation. 2016 by the Endocrine Society.
