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Showing 941–960 of 2058 publications.
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Aggarwal, Shikha; Makris, Angela; Hennessy, AnnemariePreeclampsia remains a leading cause of maternal and neonatal morbidity and mortality. The pathophysiology of preeclampsia remains poorly understood with various pathological mechanisms being implicated including the renin angiotensin system (RAAS), angiogenic pathways and various components of the immune system. Recently a pathogenic autoimmune factor has been identified in the form of auto-agonistic angiotensin II type 1 receptor antibodies (AT1-AA). AT1-AA have been studied in vitro and in vivo in various human and animal models and these data have provided compelling evidence for their role in preeclampsia. This review summarises the current literature surrounding the role of AT1-AA in preeclampsia and draws links between this relatively novel antibody to well-established pathological mechanisms including the immune system, the RAAS, angiogenic pathways and placental ischaemia. 2015 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.
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Cordina, Rachael Louise; Nakhla, Shirley; O'Meagher, Shamus; Leaney, John C.; Graham, Stuart L.; Celermajer, David S.Introduction: Cyanotic congenital heart disease is associated with functional limitation and vascular events. The nature and extent of endothelial dysfunction in cyanotic adults is poorly understood. We sought to characterise endothelial function in this setting. Methods: A total of fourteen adults with cyanotic congenital heart disease (403 years) together with age- and sex-matched healthy controls underwent assessment of nitric oxide-dependent vascular responses, including flow-mediated dilatation of the brachial artery and dynamic vessel analysis of the retina in response to flickering light. Plasma levels of the endothelium-derived vasoconstrictor endothelin-1 and the nitric oxide antagonist, asymmetric dimethylarginine, were measured. Circulating endothelial progenitor cells were assessed by flow cytometry. Results: Flow-mediated dilatation was significantly lower in cyanosed adults than controls (4.00.8 versus 7.21.0%, p=0.019, n=11 per group). Retinal arterial and venous dilatory responses were also impaired (2.90.8 versus 5.00.6%, p=0.05 and 3.40.3 versus 5.20.7%, p=0.04, n=13). Serum levels of endothelin-1 and asymmetric dimethylarginine were higher in cyanosed adults (3.00.6 versus 1.10.1 pg/ml, p=0.004 and 0.680.05 versus 0.520.02 ?mol/L, p=0.03, n=11). Endothelial progenitor cells (CD34+CD45dimCD133+KDR+) were reduced in those with chronic cyanosis (174 versus 406 per million white blood cells, p=0.005, n=11). Conclusions: Endothelial function is impaired in the systemic arteries and retinal vessels in adults with cyanotic congenital heart disease, suggesting a widespread endotheliopathy. Diminished numbers of endothelial progenitor cells might potentially contribute to these observations. Cambridge University Press 2014.
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Morgan, Philip E.; Laura, Richard P.; Maki, Richard A.; Reynolds, Wanda F.; Davies, Michael J.Elevated levels of the heme enzyme myeloperoxidase (MPO) are associated with adverse cardiovascular outcomes. MPO predominantly catalyzes formation of the oxidants hypochlorous acid (HOCl) from Cl-, and hypothiocyanous acid (HOSCN) from SCN-, with these anions acting as competitive substrates. HOSCN is a less powerful and more specific oxidant than HOCl, and selectively targets thiols; such damage is largely reversible, unlike much HOCl-induced damage. We hypothesized that increased plasma SCN-, and hence HOSCN formation instead of HOCl, may decrease artery wall damage. This was examined using high-fat fed atherosclerosis-prone LDLR-/- mice transgenic for human MPO, with and without SCN- (10 mM) added to drinking water. Serum samples, collected fortnightly, were analyzed for cholesterol, triglycerides, thiols, MPO, and SCN-; study-long exposure was calculated by area under the curve (AUC). Mean serum SCN- concentrations were elevated in the supplemented mice (200-320 ?M) relative to controls (< 120 ?M). Normalized aortic root plaque areas at sacrifice were 26% lower in the SCN--supplemented mice compared with controls (P = 0.0417), but plaque morphology was not appreciably altered. Serum MPO levels steadily increased in mice on the high-fat diet, however, comparison of SCN--supplemented versus control mice showed no significant changes in MPO protein, cholesterol, or triglyceride levels; thiol levels were decreased in supplemented mice at one time-point. Plaque areas increased with higher cholesterol AUC (r = 0.4742; P = 0.0468), and decreased with increasing SCN- AUC (r = - 0.5693; P = 0.0134). These data suggest that increased serum SCN- levels, which can be achieved in humans by dietary manipulation, may decrease atherosclerosis burden. 2015 Informa UK, Ltd.
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Hawkins, Clare L.; Van Antwerpen, Pierre[No abstract available]
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Carroll, Luke; Davies, Michael J.; Pattison, David I.Selenium is an essential trace element in mammals, with the majority specifically encoded as seleno-L-cysteine into a range of selenoproteins. Many of these proteins play a key role in modulating oxidative stress, via either direct detoxification of biological oxidants, or repair of oxidised residues. Both selenium- and sulphur-containing residues react readily with the wide range of oxidants (including hydrogen peroxide, radicals, singlet oxygen and hypochlorous, hypobromous, hypothiocyanous and peroxynitrous acids) that are produced during inflammation and have been implicated in the development of a range of inflammatory diseases. Whilst selenium has similar properties to sulphur, it typically exhibits greater reactivity with most oxidants, and there are considerable differences in the subsequent reactivity and ease of repair of the oxidised species that are formed. This review discusses the chemistry of low-molecular-mass organoselenium compounds (e.g. selenoethers, diselenides and selenols) with inflammatory oxidants, with a particular focus on the reaction kinetics and product studies, with the differences in reactivity between selenium and sulphur analogues described in the selected examples. These data provide insight into the therapeutic potential of low-molecular-mass selenium-containing compounds to modulate the activity of both radical and molecular oxidants and provide protection against inflammation-induced damage. Progress in their therapeutic development (including modulation of potential selenium toxicity by strategic design) is demonstrated by a brief summary of some recent studies where novel organoselenium compounds have been used as wound healing or radioprotection agents and in the prevention of cardiovascular disease. 2015 Informa UK, Ltd.
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Low zinc and selenium concentrations in sepsis are associated with oxidative damage and inflammationMertens, K.; Lowes, Damon A.; Webster, Nigel R.; Talib, Jihan; Hall, L.; Davies, Michael J.; Beattie, John H.; Galley, Helen F.Background: Oxidative stress with dysregulated inflammation are hallmarks of sepsis. Zinc and selenium have important antioxidant functions, such that they could be important in patients with sepsis. We used an in vitro approach to assess the effect of zinc and selenium on oxidative stress, mitochondrial function, and inflammatory responses in conditions mimicking sepsis and related the findings to plasma concentrations and biomarkers in patients with and without sepsis. Methods: Human endothelial cells were exposed to a range of zinc and selenium concentrations in conditions mimicking sepsis. Zinc, selenium, and a series of biomarkers of oxidative stress and inflammationwere measured in plasma from critically ill patients with and without sepsis. Results: Culturing cells with different concentrations of zinc caused altered zinc transporter protein expression and cellular zinc content, and selenium affected glutathione peroxidase 3 activity. Although zinc or selenium at physiological concentrations had no effect on interleukin-6 release in vitro, higher concentrations of the trace elements were associated with improved mitochondrial function. Plasma zinc and selenium concentrations were low in patients [zinc: median (range) 4.6 (2.1-6.5) ?M in control patients without sepsis and 3.1 (1.5-5.4) ?M in patients with sepsis, P=0.002; and selenium: 0.78 (0.19- 1.32) ?M in control patients and 0.42 (0.22-0.91) ?M in sepsis patients, P=0.0009]. Plasma concentrations of interleukin-6, other biomarkers of inflammation, and markers of oxidative damage to proteins and lipidswere elevated, particularly in patients with sepsis, and were inversely related to plasma zinc and selenium concentrations. Conclusions: Zinc and selenium concentrations were reduced in critically ill patients, with increased oxidative stress and inflammatory biomarkers, particularly in patients with sepsis. Oxidative stress as a result of suboptimal selenium and zinc concentrations might contribute to damage of key proteins. Clinical trial registration: ClinicalTrials.gov: registration number NCT01328509. The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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Farnham, M. M. J.; O'Connor, Edward T.; Wilson, Richard J.A.; Pilowsky, Paul M.Background: The explosion in the use of genetically modified mouse strains to investigate function in biology has an enormous potential to expand on pharmacological studies traditionally conducted in rats. A key limitation to date is the inability to record from multiple nerves in an anaesthetised mouse for long periods. New method: Here we describe an in vivo preparation that maintains mice in a suitable physiological state, under anaesthesia, for at least 6hr and also enables multiple cardiorespiratory recordings over that time. Results: Using the method described, blood pressure, heart rate, phrenic nerve activity, splanchnic nerve activity and heart rate were able to be recorded for hours in an anaesthetised, paralysed and mechanically ventilated mouse. Comparison with existing method: Existing anaesthetised mouse preparations are limited by difficulties in maintaining mice under anaesthesia for long periods. This time constraint therefore limits the surgical time and number of cardiorespiratory variables recorded. It also limits the type of stimuli that can be administered and the length of recorded responses. The method described here optimises these variables to overcome these challenges. Conclusions: In summary, we report an approach that enables physiological and pharmacological studies previously undertaken in larger animals or 'reduced' preparations, to be conducted in vivo in mice. We anticipate that the use of this preparation will enable a deeper understanding of genetic variation, and allow a much greater level of phenotypic characterisation in genetically modified mice. 2015 Elsevier B.V.
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Yao, Yimin; Hildreth, Cara M.; Farnham, M. M. J.; Saha, Manash; Sun, Qijian; Pilowsky, Paul M.; Phillips, Jacqueline K.Background: The effect of angiotensin II type I receptor (AT 1 R) inhibition on the pattern of reflex sympathetic nerve activity (SNA) to multiple target organs in the Lewis polycystic kidney (LPK) rat model of chronic kidney disease was determined. Methods: Mean arterial pressure (MAP), splanchnic SNA (sSNA), renal SNA (rSNA) and lumbar SNA (lSNA) were recorded in urethane-anaesthetized LPK and Lewis controls (total n = 39). Baroreflex, peripheral and central chemoreflex, and somatosensory reflex control of SNA (evoked by phenylephrine/sodium nitroprusside infusion, 10% O 2 in N 2 or 100% N 2 ventilation, 5% CO 2 ventilation and sciatic nerve stimulation, respectively) were determined before and after administration of losartan (AT 1 R antagonist 3 mg/kg, intravenous). Results: Baseline MAP was higher in LPK rats and baroreflex control of sSNA and rSNA, but not lSNA, was reduced. Losartan reduced MAP in both strains and selectively improved baroreflex gain for sSNA (-1.2 0.1 vs. -0.7 0.07 %/mmHg; P < 0.05) in LPK. The peripheral and central chemoreflex increased MAP and all SNA in Lewis controls, but reduced or had no effect on these parameters, respectively, in LPK. The SNA response to somatosensory stimulation was biphasic, with latency to second peak less in LPK. Losartan ameliorated the depressor and sympathoinhibitory responses to peripheral chemoreflex stimulation in the LPK, but did not alter the central chemoreflex or somatosympathetic responses. Conclusion: Inhibition of the AT 1 R selectively improved baroreflex control of sSNA and peripheral chemoreflex control of all three sympathetic nerve outflows in the LPK rat, suggesting these anomalies in reflex function are driven in part by angiotensin II. 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Yu, Young; Wise, Steven G.; Michael, Praveesuda Lorwattanapongsa; Bax, Daniel V.; Yuen, Gloria S.C.; Hiob, Matti A.; Yeo, Giselle C.; Filipe, Elysse C.; Dunn, Louise L.; Chan, Kim Hoe; Hajian, Hamid; Celermajer, David S.; Weiss, Anthony Steven; Ng, Martin K.C.The deployment of endovascular implants such as stents in the treatment of cardiovascular disease damages the vascular endothelium, increasing the risk of thrombosis and promoting neointimal hyperplasia. The rapid restoration of a functional endothelium is known to reduce these complications. Circulating endothelial progenitor cells (EPCs) are increasingly recognized as important contributors to device re-endothelialization. Extracellular matrix proteins prominent in the vessel wall may enhance EPC-directed re-endothelialization. We examined attachment, spreading and proliferation on recombinant human tropoelastin (rhTE) and investigated the mechanism and site of interaction. EPCs attached and spread on rhTE in a dose dependent manner, reaching a maximal level of 563% and 543%, respectively. EPC proliferation on rhTE was comparable to vitronectin, fibronectin and collagen. EDTA, but not heparan sulfate or lactose, reduced EPC attachment by 813%, while full attachment was recovered after add-back of manganese, inferring a classical integrin-mediated interaction. Integrin ?<inf>V</inf>?<inf>3</inf> blocking antibodies decreased EPC adhesion and spreading on rhTE by 393% and 5610% respectively, demonstrating a large contribution from this specific integrin. Attachment of EPCs on N-terminal rhTE constructs N25 and N18 accounted for most of this interaction, accompanied by comparable spreading. In contrast, attachment and spreading on N10 was negligible. ?<inf>V</inf>?<inf>3</inf> blocking antibodies reduced EPC spreading on both N25 and N18 by 454% and 4214%, respectively. In conclusion, rhTE supports EPC binding via an integrin mechanism involving ?<inf>V</inf>?<inf>3</inf>. N25 and N18, but not N10 constructs of rhTE contribute to EPC binding. The regulation of EPC activity by rhTE may have implications for modulation of the vascular biocompatibility of endovascular implants. 2015 Yu 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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Indo, Hiroko P.; Matsui, Hirofumi; Chen, Jing; Zhu, Haining; Hawkins, Clare L.; Davies, Michael J.; Yarana, Chontida; St. Clair, Daret K.; Majima, Hideyuki J.It hasbeendemonstratedthatcancercells areunderhigh levels of oxidative stress and express high levels of Manganese superoxide dismutase (MnSOD) to protect themselves and support the anabolic metabolism needed for growth and cell motility. The aim of this study was to identify proteins that may have a correlation with invasion and redox regulation by mitochondrial reactive oxygen species (ROS). MnSOD scavenges superoxide anions generated from mitochondria and is an important regulator of cellular redox status. Oxidative posttranslational modification of cysteine residues is a key mechanism that regulates protein structure and function. We hypothesized that MnSOD regulates intracellular reduced thiol status and promotes cancer invasion. A proteomic thiol-labeling approach with 5-iodoacetamidofluores-cein was used to identify changes in intracellular reduced thiol-containing proteins. Our results demonstrate that overexpression of MnSOD maintained the major structural protein, actin, in a reduced state, and enhanced the invasion ability in gastric mucosal cancer cells, RGK1. We also found that the expression of Talin and S100A4 were increased in MnSOD-overexpressed RGK1 cells. Moreover, Talin bound not only with actin but also with S100A4, suggesting that the interaction of these proteins may, in part, contribute to the invasive ability of rat gastric cancer. 2015 JCBN.
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Wu, Ben Jing; Shrestha, Sudichhya; Ong, Kwok Leung; Johns, Douglas G.; Dunn, Louise L.; Hou, Liming; Barter, Philip J.; Rye, Kerry AnneBackground High density lipoprotein (HDL) infusions increase new blood vessel formation (angiogenesis) in rodents with ischemic injury. This study asks if increasing HDL levels by inhibiting cholesteryl ester transfer protein (CETP) activity increases angiogenesis in New Zealand White (NZW) rabbits with hindlimb ischemia. Methods and results NZW rabbits were maintained for 6 weeks on chow or chow supplemented with 0.07% or 0.14% (wt/wt) of the CETP inhibitor, des-fluoro-anacetrapib. The left femoral artery was ligated after 2 weeks of des-fluoro-anacetrapib treatment. The animals were sacrificed 4 weeks after femoral artery ligation. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib reduced CETP activity by 63 12% and 81 8.6%, increased plasma apoA-I levels by 1.3 0.1- and 1.4 0.1-fold, and increased plasma HDL-cholesterol levels by 1.4 0.1- and 1.7 0.2-fold, respectively. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib increased the number of collateral arteries by 60 16% and 84 27%, and arteriole wall area in the ischemic hindlimbs by 84 16% and 94 13%, respectively. Capillary density in the ischemic hindlimb adductor muscle increased from 1.1 0.2 (control) to 2.1 0.3 and 2.2 0.4 in the 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib-treated animals, respectively. Incubation of HDLs from des-fluoro-anacetrapib-treated animals with human coronary artery endothelial cells at apoA-I concentrations comparable with their plasma levels increased tubule network formation. These effects were abolished by knockdown of scavenger receptor-B1 (SR-B1) and PDZK1, and pharmacological inhibition of PI3K/Akt. Conclusion Increasing HDL levels by inhibiting CETP activity is associated with increased collateral blood vessel formation in NZW rabbits with hindlimb ischemia in an SR-B1- and PI3K/Akt-dependent manner. 2015 Elsevier Ireland Ltd. All rights reserved.
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Kaplan, Zane S.; Zarpellon, Alessandro; Alwis, Imala D.; Yuan, Yuping; McFadyen, James D.; Ghasemzadeh, Mehran; Schoenwaelder, Simone M.; Ruggeri, Zaverio M.; Jackson, Shaun P.Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIb? and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIb?, as seen in mice with abrogated thrombin-platelet GPIb? binding (hGPIb? D277N). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIb? and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders. 2015 Macmillan Publishers Limited.
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Vaidya, Kaivan; Arnott, Clare; Russell, Anne; Masson, Philip; Sy, Raymond W.; Patel, SanjayBackground: Atrial fibrillation (AF) often coexists with congestive cardiac failure (CCF), with multiple treatment options available. Methods: Systematic review and meta-analysis of randomised control trials (RCT) comparing pulmonary vein isolation (PVI), pharmacological rate control, and atrioventricular junction ablation with pacemaker insertion (AVJAP) for AF, with a subgroup analysis in patients with CCF. We analysed changes in left ventricular ejection fraction (LVEF), Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, six-minute walk distance (6MWD), treadmill exercise time, and treatment complications. Results were expressed as weighted mean differences (WMD) with 95% Confidence-Intervals (95%CI). Results: We included seven RCT (425 participants). PVI was associated with a greater increase in LVEF (WMD+6.5%, 95%CI:+0.6to+12.5) and decrease in MLHFQ score (WMD-11.0, 95%CI:-2.6to-19.4) than pharmacological rate control in patients with CCF. PVI was also associated with a greater increase in LVEF (WMD+9.0%, 95%CI:+6.3to+11.7) and 6MWD (WMD+55.0metres, 95%CI:+34.9to+75.1), and decrease in MLHFQ score (WMD-22.0, 95%CI:-17.0to-27.0), compared to AVJAP in patients with CCF. Irrespective of cardiac function, pharmacological rate control had similar effects to AVJAP on LVEF (WMD+0.6%, 95%CI:-8.3to+9.4) and treadmill exercise time (WMD+0.5. minutes, 95%CI:-0.4to+1.3). Conclusions: Our results support the clinical implementation of PVI over AVJAP or pharmacological rate control in AF patients with CCF, who may or may not have already trialled pharmacological rhythm control. 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
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Parker, Helen M.; O'Connor, Helen T.; Keating, Shelley E.; Cohn, Jeffrey S.; Garg, Manohar Lal; Caterson, Ian Douglas; George, Jacob A.; Johnson, Nathan A.Non-alcoholic fatty liver disease (NAFLD) is an independent predictor of CVD in otherwise healthy individuals. Low n-3 PUFA intake has been associated with the presence of NAFLD; however, the relationship between a biomarker of n-3 status - the Omega-3 Index - and liver fat is yet to be elucidated. A total of eighty overweight adults (fifty-six men) completed the anthropometric and biochemical measurements, including the Omega-3 Index, and underwent proton magnetic resonance spectroscopy assessment of liver fat. Bivariate correlations and multiple regression analyses were performed with reference to prediction of liver fat percentage. The mean Omega-3 Index was high in both NAFLD (intrahepatic lipid concentration?55 %) and non-NAFLD groups. The Omega-3 Index, BMI, waist circumference, glucose, insulin, TAG, high-sensitive C-reactive protein (hsCRP) and alanine aminotransferase (ALT) were positively correlated, and HDL and erythrocyte n-6:n-3 ratio negatively correlated with liver fat concentration. Regression analysis found that simple anthropometric and demographic variables (waist, age) accounted for 31 % of the variance in liver fat and the addition of traditional cardiometabolic blood markers (TAG, HDL, hsCRP and ALT) increased the predictive power to 43 %. The addition of the novel erythrocyte fatty acid variable (Omega-3 Index) to the model only accounted for a further 3 % of the variance (P=0049). In conclusion, the Omega-3 Index was associated with liver fat concentration but did not improve the overall capacity of demographic, anthropometric and blood markers to predict NAFLD. 2015 The Authors.
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Clayton, Zoe E.; Sadeghipour, Sara; Patel, SanjayStandard therapy for atherosclerotic coronary and peripheral arterial disease is insufficient in a significant number of patients because extensive disease often precludes effective revascularization. Stem cell therapy holds promise as a supplementary treatment for these patients, as pre-clinical and clinical research has shown transplanted cells can promote angiogenesis via direct and paracrine mechanisms. Induced pluripotent stem cells (iPSCs) are a novel cell type obtained by reprogramming somatic cells using exogenous transcription factor cocktails, which have been introduced to somatic cells via viral or plasmid constructs, modified mRNA or small molecules. IPSCs are now being used in disease modelling and drug testing and are undergoing their first clinical trial, but despite recent advances, the inefficiency of the reprogramming process remains a major limitation, as does the lack of consensus regarding the optimum transcription factor combination and delivery method and the uncertainty surrounding the genetic and epigenetic stability of iPSCs. IPSCs have been successfully differentiated into vascular endothelial cells (iPSC-ECs) and, more recently, induced endothelial cells (iECs) have also been generated by direct differentiation, which bypasses the pluripotent intermediate. IPSC-ECs and iECs demonstrate endothelial functionality in vitro and have been shown to promote neovessel growth and enhance blood flow recovery in animal models of myocardial infarction and peripheral arterial disease. Challenges remain in optimising the efficiency, safety and fidelity of the reprogramming and endothelial differentiation processes and establishing protocols for large-scale production of clinical-grade, patient-derived cells. 2015 Elsevier Ireland Ltd.
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Martez, Gonzalo J.; Robertson, Stacy; Barraclough, Jennifer Y.; Xia, Qiong; Mallat, Ziad; Bursill, C. A.; Celermajer, David S.; Patel, SanjayBACKGROUND: Interleukin (IL)-1?, IL-18, and downstream IL-6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP3 inflammasome, a cytosolic complex responsible for the production of IL-1? and IL-18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes (ACS), stable coronary artery disease and in controls; and (2) determine whether acute administration of colchicine inhibits their production.METHODS AND RESULTS: Forty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood samples from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL-1?, IL-18, and IL-6 using ELISA. In ACS patients, coronary sinus levels of IL-1?, IL-18, and IL-6 were significantly higher than arterial and venous levels (P=0.017, <0.001 and <0.001, respectively). Transcoronary (coronary sinus-arterial) gradients for IL-1?, IL-18, and IL-6 were highest in ACS patients and lowest in controls (P=0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (P=0.028, 0.032, and 0.032, for IL-1?, IL-18, and IL-6, respectively).CONCLUSIONS: ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short-term colchicine administration rapidly and significantly reduces levels of these cytokines. 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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Colchicine in cardiac disease: A systematic review and meta-analysis of randomized controlled trialsVerma, Subodh G.; Eikelboom, John W.; Nidorf, Stefan Mark; Al-Omran, Mohammed; Gupta, Nandini; Teoh, Hwee; Friedrich, Jan O.Background: Colchicine has unique anti-inflammatory properties that may be beneficial in various cardiovascular conditions. This systematic review and meta-analysis of randomized controlled trials (RCTs) examines this issue. Methods: We searched MEDLINE, EMBASE, and the Cochrane Database from inception to June 2014 for RCTs using colchicine in adult patients with cardiac diseases. Results were pooled using random effects. Results: 15 RCTs (n = 3431 patients, median treatment 3 and follow-up 15 months) were included. All but 2 used colchicine 1 mg/day. In 5 trials, n = 1301) at risk for cardiovascular disease (coronary artery disease, acute coronary syndrome or stroke, post-angioplasty [2 RCTs], or congestive heart failure), colchicine reduced composite cardiovascular outcomes by ~60 % (risk ratio [RR] 0.44, 95 % confidence interval [CI] 0.28-0.69, p=0.0004; I2=0 %) and showed a trend towards lower all-cause mortality (RR 0.50, 95 % CI 0.23-1.08, p=0.08; I2=0 %). In pericarditis or post-cardiotomy, colchicine decreased recurrent pericarditis or post-pericardiotomy syndrome (RR 0.50, 95 % CI 0.41-0.60, p<0.0001; I2=0 %; 8 RCTs, n=1635), and post-pericardiotomy or ablation induced atrial fibrillation (RR 0.65, 95 % CI 0.51-0.82, p=0.0003; I2=31 %; 4 RCTs, n=1118). The most common adverse event was diarrhea. Treatment discontinuation overall and due to adverse events (RR 4.34, 95 % CI 1.70-11.07, p=0.002; I2=29 %; 7 RCTs, 83/790 [10.5 %] vs. 11/697 [1.6 %]) was higher in colchicine-assigned patients. Conclusions: Current RCT data suggests that colchicine may reduce the composite rate of cardiovascular adverse outcomes in a range of patients with established cardiovascular disease. Furthermore, colchicine reduces rates of recurrent pericarditis, post-pericardiotomy syndrome, and peri-procedural atrial fibrillation following cardiac surgery. Further RCTs evaluating the potential of colchicine for secondary prevention of cardiovascular events would be of interest. 2015 Verma et al.
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Ju, Lining Arnold; Chen, Yunfeng; Zhou, Fangyuan; Lu, Hang; Cr, Miguel Angel; Zhu, ChengCirculating von Willebrand factor (VWF) adopts a closed conformation that shields the platelet glycoprotein Ib? (GPIb?) binding site in the VWF-A1 domain. Immobilized at sites of vascular injury, VWF is activated by its interaction with collagen and the exertion of increased hemodynamic forces. Studies on native VWF strings and isolated A1 domains suggest the existence of multiple A1 binding states in different biophysical contexts. In this single-molecule study, we have used a biomembrane force probe (BFP) and a flow chamber to identify and characterize a collagen binding induced conformation with a higher affinity to platelet GPIb?. As force increases, our results show that collagen binding increases the stability of GPIb? bond with both VWF and isolated A1 domain. However, the collagen 2D binding affinity for VWF-A3 domain is 10 times of that for A1 domain, suggesting the initial VWF capture is mediated by A3-collagen interaction while A1-collagen regulates the subsequent VWF activation. Our results reveal the molecular mechanism of collagen-regulated, A1-mediated platelet adhesion enhancement. Characterization of different A1 states provides insights into binding heterogeneity of VWF in different scenarios of inflammation and thrombosis. 2015 Elsevier Ltd.
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Boon, Ai Ching; Hawkins, Clare L.; Coombes, Jeff S.; Wagner, Karl Heinz; Bulmer, Andrew CameronHypochlorous acid (HOCl), an oxidant produced by myeloperoxidase (MPO), induces protein and lipid oxidation, which is implicated in the pathogenesis of atherosclerosis. Individuals with mildly elevated bilirubin concentrations (i.e., Gilbert syndrome; GS) are protected from atherosclerosis, cardiovascular disease, and related mortality. We aimed to investigate whether exogenous/endogenous unconjugated bilirubin (UCB), at physiological concentrations, can protect proteins/lipids from oxidation induced by reagent and enzymatically generated HOCl. Serum/plasma samples supplemented with exogenous UCB (>&250 ?&M) were assessed for their susceptibility to HOCl and MPO/H;bsubesubbsubesubbsupesup oxidation, by measuring chloramine, protein carbonyl, and malondialdehyde (MDA) formation. Serum/plasma samples from hyperbilirubinemic Gunn rats and humans with GS were also exposed to MPO/H;bsubesubbsubesubbsupesup to: (1) validate in vitro data and (2) determine the relevance of endogenously elevated UCB in preventing protein and lipid oxidation. Exogenous UCB dose-dependently (P<0.05) inhibited HOCl and MPO/H;bsubesubbsubesubbsupesup-induced chloramine formation. Albumin-bound UCB efficiently and specifically (3.9-125 ;mu P<0.05) scavenged taurine, glycine, and N-?-acetyllysine chloramines. These results were translated into Gunn rat and GS serum/plasma, which showed significantly (P<0.01) reduced chloramine formation after MPO-induced oxidation. Protein carbonyl and MDA formation was also reduced after MPO oxidation in plasma supplemented with UCB (P;lt 25 and 50 ?M, respectively). Significant inhibition of protein and lipid oxidation was demonstrated within the physiological range of UCB, providing a hypothetical link to protection from atherosclerosis in hyperbilirubinemic individuals. These data demonstrate a novel and physiologically relevant mechanism whereby UCB could inhibit protein and lipid modification by quenching chloramines induced by MPO-induced HOCl. copy; 2015 Elsevier Inc. All rights reserved.
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Ong, Kwok Leung; Januszewski, Andrzej S.; OConnell, Rachel; Buizen, Luke; Jenkins, Alicia J.; Xu, Aimin; Sullivan, David R.; Barter, Philip J.; Scott, R. S.; Taskinen, Marja Riitta; Rye, Kerry Anne; Keech, Anthony C.Aims/hypothesis: Baseline circulating fibroblast growth factor 21 (FGF21) levels can predict total cardiovascular disease events in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. This paper describes the relationship of baseline FGF21 levels and new on-study microvascular disease in patients with type 2 diabetes from the FIELD study. Methods: Baseline FGF21 levels were measured in plasma by enzyme-linked immunosorbent assay in 9697 study participants. Total microvascular disease was defined as the presence of any nephropathy, retinopathy, neuropathy and/or microvascular amputation. The relationship between FGF21 levels and microvascular disease was assessed by multivariable logistic regression. Results: Higher baseline FGF21 levels were found in patients with baseline total microvascular disease (p < 0.001). The association remained significant after adjusting for potential confounding factors (OR [95% CI] 1.13 [1.08, 1.19] per SD increase in log<inf>e</inf>-transformed FGF21 levels, p < 0.001). Of 6465 patients without baseline total microvascular disease, 1517 developed new on-study total microvascular disease over 5years of follow-up. Higher baseline FGF21 levels were associated with a higher risk of new on-study total microvascular disease after adjusting for potential confounding factors (OR [95% CI] 1.09 [1.02, 1.16] per SD increase in log<inf>e</inf>-transformed FGF21 levels, p = 0.01). Addition of FGF21 levels in a model of new on-study total microvascular disease with established risk factors significantly, but modestly, increased the integrated discrimination improvement and the net reclassification improvement (both p < 0.01). Conclusions/interpretation: Higher baseline FGF21 levels are seen in patients with type 2 diabetes and established microvascular disease, and predict the future development of new microvascular disease. 2015, Springer-Verlag Berlin Heidelberg.
