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Showing 721–740 of 2058 publications.
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Cao, Lei; Graham, Stuart L.; Pilowsky, Paul M.Background It is reported that glaucoma may be associated with vascular dysregulation. Normal tension glaucoma (NTG) and primary open angle glaucoma (POAG), which feature different intraocular pressure levels, may manifest differential features of systemic autonomic dysregulation. Methods and results We investigated autonomic regulation to carbohydrate ingestion and postural change in 37 glaucoma patients (19 NTG and 18 POAG) and 36 controls. Subjects were age and gender-matched, normotensive, and had normal comparable insulin sensitivity. Continuous finger arterial pressure and ECG was recorded in supine and standing positions before and after carbohydrate ingestion. Low frequency (LF, 0.040.15Hz) and high frequency (HF, 0.150.4Hz) spectral power of heart rate and systolic blood pressure variability (HRV and SBPV) were calculated to estimate sympathovagal function. Overall comparison glaucoma (N = 37) and controls (N = 36) showed an increased sympathetic excitation, vagal withdrawal and unstable mean arterial pressure after carbohydrate ingestion in glaucoma patients. Glaucoma severity by retinal nerve fibre layer (RNFL) thickness is positively correlated to autonomic responses (HRV LF power and HF power in normalised units (nu), and HRV LF/HF ratio) after carbohydrate ingestion. Early (30 minutes) following carbohydrate ingestion, SBP LF power and HRV parameters remained unchanged in controls; while POAG showed abnormal autonomic responses, with a paradoxical vagal enhancement (increased HRV HF power in nu) and sympathetic inhibition (decreased HRV LF power nu and HRV LF/HF ratio), and associated hypotension. Later (60120 minutes) following carbohydrate ingestion, HRV parameters remained unaltered in controls; whereas NTG manifested vagal withdrawal (reduced HRV HF power nu) and sympathetic hyper-responsiveness (increased HRV LF power nu and HRV LF/HF ratio), despite increased SBP LF power in both controls and NTG. Both NTG and POAG exhibited attenuated autonomic responses to postural stress. Conclusions NTG and POAG both manifest some systemic autonomic cardiovascular dysregulation. However, the two forms of glaucoma respond differentially to carbohydrate ingestion, irrespective of insulin resistance. 2018 Cao 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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Vanags, Laura Z.; Tan, Joanne Tsui Ming; Galougahi, Keyvan Karimi; Schaefer, Andreas; Wise, Steven G.; Murphy, Andrew James; Ali, Ziad A.; Bursill, C. A.Even the most advanced drug-eluting stents evoke unresolved issues, including chronic inflammation, late thrombosis, and neoatherosclerosis. This highlights the need for novel strategies that improve stent biocompatibility. Our studies show that apolipoprotein A-I (apoA-I) reduces in-stent restenosis and platelet activation, and enhances endothelialization. These findings have therapeutic implications for improving stent biocompatibility. 2018 The Authors
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Bobek, Gabriele; Stait-Gardner, Timothy; Price, William S.; Makris, Angela; Hennessy, AnnemarieAbnormal development of the placenta is postulated to be central to the aetiology of preeclampsia. This study investigates changes in placental histopathology in mouse models of preeclampsia compared to the morphology using magnetic resonance microscopy (MRM) (11.7 T) of intact ex vivo tissue followed by 3D analysis of the image data. Here, C57BL/6JArc pregnant mice were subject to either normal pregnancy (n=3), or to one of two experimental models of preeclampsia; TNF-? infusion (n=3) or reduced uterine perfusion pressure (RUPP) (n=3). Placental tissue was collected at gestational day (gd) 17, fixed in formalin and incubated with Magnavist contrast agent, and high resolution images (50 ?m 50 ?m 50 ?m voxels) obtained by magnetic resonance imaging at 11.74 T. Visual segmentation into placental subregions and three dimensional (3D) reconstruction followed by volume analysis was performed with Amira 3D analysis software. The significance of differences between treatment groups in total and regional volumes was assessed. In a single placenta the volumes measure by standard histology were compared. Three placentas from each animal were imaged, segmented into anatomical regions and 3D reconstructions generated. Total placental volume, labyrinth and decidual volume were not significantly different between groups. The junctional zone volume was found to be significantly larger in the RUPP animals (18.51.5 mm3) compared to TNF-? infused animals (15.81.5) or control animals (15.00.7, P<0.01). However, the decidual/junctional zone volume was smaller in the TNF-a compared to control animals (P<0.05). Placental structural change in experimental models of preeclampsia is able to be visualized and quantified using MRM and 3-D analysis. These techniques could prove to be a powerful tool in examining changes in placental morphology. G. Bobek et al., 2018.
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Yan, Bryan Ping Yen; Lai, William H.S.; Chan, Christy K.Y.; Chan, Stephen Chun Hin; Chan, Lok Hei; Lam, Ka Ming; Lau, Howang; Ng, Chak Ming; Tai, Lok Yin; Yip, Kin Wai; To, Olivia Tsz Ling; Freedman, Ben Ben; Poh, Yukkee Cheung; Poh, Ming ZherBackground-We aimed to evaluate a novel method of atrial fibrillation (AF) screening using an iPhone camera to detect and analyze photoplethysmographic signals from the face without physical contact by extracting subtle beat-to-beat variations of skin color that reflect the cardiac pulsatile signal. Methods and Results-Patients admitted to the cardiology ward of the hospital for clinical reasons were recruited. Simultaneous facial and fingertip photoplethysmographic measurements were obtained from 217 hospital inpatients (mean age, 70.313.9 years; 71.4% men) facing the front camera and with an index finger covering the back camera of 2 independent iPhones before a 12-lead ECG was recorded. Backdrop and background light intensity was monitored during signal acquisition. Three successive 20-second (total, 60 seconds) recordings were acquired per patient and analyzed for heart rate regularity by Cardiio Rhythm (Cardiio Inc, Cambridge, MA) smartphone application. Pulse irregularity in ?1 photoplethysmographic readings or 3 uninterpretable photoplethysmographic readings were considered a positive AF screening result. AF was present on 12-lead ECG in 34.6% (n=75/217) patients. The Cardiio Rhythm facial photoplethysmographic application demonstrated high sensitivity (95%; 95% confidence interval, 87%-98%) and specificity (96%; 95% confidence interval, 91%-98%) in discriminating AF from sinus rhythm compared with 12-lead ECG. The positive and negative predictive values were 92% (95% confidence interval, 84%-96%) and 97% (95% confidence interval, 93%-99%), respectively. Conclusions--Detection of a facial photoplethysmographic signal to determine pulse irregularity attributable to AF is feasible. The Cardiio Rhythm smartphone application showed high sensitivity and specificity, with low negative likelihood ratio for AF from facial photoplethysmographic signals. The convenience of a contact-free approach is attractive for community screening and has the potential to be useful for distant AF screening. 2018 The Authors.
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Watson, Emma E.; Liu, Xuyu; Thompson, Robert E.; Ripoll-Rozada, Jorge; Wu, Mike C.L.; Alwis, Imala D.; Gori, Alessandro; Loh, Choy Theng; Parker, Benjamin L.; Otting, Gottfried; Jackson, Shaun P.; Pereira, Pedro JosBarbosa; Payne, Richard J.The anophelins are small protein thrombin inhibitors that are produced in the salivary glands of the Anopheles mosquito to fulfill a vital role in blood feeding. A bioinformatic analysis of anophelin sequences revealed the presence of conserved tyrosine residues in an acidic environment that were predicted to be post-translationally sulfated in vivo. To test this prediction, insect cell expression of two anophelin proteins, from Anopheles albimanus and Anopheles gambiae, was performed, followed by analysis by mass spectrometry, which showed heterogeneous sulfation at the predicted sites. Homogeneously sulfated variants of the two proteins were subsequently generated by chemical synthesis via a one-pot ligation-desulfurization strategy. Tyrosine sulfation of the anophelins was shown to significantly enhance the thrombin inhibitory activity, with a doubly sulfated variant of the anophelin from A. albimanus exhibiting a 100-fold increase in potency compared with the unmodified homologue. Sulfated anophelins were also shown to exhibit potent in vivo anticoagulant and antithrombotic activity. 2018 American Chemical Society.
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Kwok, Chi Ho Ricky; Fleming, Scott; Chan, Kenneth K.C.; Tibballs, Jonathan M.; Samuelson, Shaun D.; Ferguson, John M.; Nadkarni, Sanjay; Hockley, Joseph Allan; Jansen, Shirley JanePurpose: To examine the efficacy, safety, and procedural costs of percutaneous aspiration thrombectomy (PAT) as a first-line treatment for noniatrogenic acute lower limb ischemia (ALI) compared with conventional catheter-directed thrombolysis (CDT). Materials and Methods: All patients who underwent endovascular intervention for ALI from January 2015 to August 2017 were included. Fifteen patients were treated with the use of primary PAT and 27 patients were treated with the use of primary CDT. The primary end point was complete thrombus clearance with improvement in Thrombolysis in Myocardial Infarction (TIMI) score. Adjunctive treatment for thrombus removal was considered to indicate technical failure. Treatment of underlying chronic disease was not considered to indicate technical failure. Procedural costs for each patient were calculated by itemizing all disposable equipment, facility overheads, and staff costs. Results: Of the 15 primary PAT patients, technical success was achieved in 8 (53%); the remaining 7 (47%) required adjunctive CDT. Of the 27 primary CDT patients, technical success was achieved in 25 (89%); the remaining 2 (11%) required adjunctive PAT. There were 4 complications in the primary PAT group: 2 were procedure related and of a minor grade. There were 8 complications in the primary CDT group: All were procedure-related, including 2 major groin/retroperitoneal hemorrhage and 1 death from intracranial hemorrhage. Limb salvage was attained in all patients. There were no significant differences in average procedural costs per patient between the 2 groups. Conclusions: First-line use of PAT for endovascular treatment of ALI can reduce the need for CDT, with no significant cost difference. 2017
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Li, Jialin; Lowres, Nicole; Jin, Kai; Zhang, Ling; Neubeck, Lis; Gallagher, Robyn D.Background: Chinese immigrants are at an increased risk for cardiovascular diseases (CVDs) compared with Chinese nationals partly because of lifestyle changes and knowledge deficits. Translated patient resources are available on the Internet and are often provided by health professionals; however, the quality and cultural sensitivity of these resources have not been reported. Objective: The aim of this study was to assess the availability, quality, and cultural sensitivity of Chinese-language information available from national "Heart Foundations" (cardiac research bodies, nongovernmental organisations) of the 5 most popular destinations of Chinese immigration. Methods: This study is a descriptive research in which national "Heart Foundation" websites were systematically searched for Chinese-language CVD patient education resources. Quality (content, identification, structure) was assessed using the Ensuring Quality Information for Patients instrument. Cultural sensitivity was evaluated using the Cultural Sensitivity Assessment Tool. Results: From 107 identified resources, 33 were CVD specific: coronary heart disease (n = 20), arrhythmias (n = 7), and heart failure (n = 6). Quality of resources was adequate (mean Ensuring Quality Information for Patients score, 69%), but scores varied significantly (min, 60%; max, 85%). Although all resources were classified as culturally sensitive (Cultural Sensitivity Assessment Tool score ? 2.5), 2 resources scored low (?2.5) for visual impact, and across all resources, written and visual domains were assessed as least culturally sensitive. Most resources lacked culturally specific references. Conclusions: Chinese-language CVD resources were inconsistent in the supply of key information. Quality and level of cultural sensitivity were adequate, but most resources lacked culturally specific references. Comprehensive, high-quality CVD resources powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation tailored for Chinese immigrants are urgently needed for healthcare providers to support CVD education and care of patients belonging to this population. 2018 Wolters Kluwer Health, Inc. All rights reserved.
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Joseph, Simon Z.; Kwok, Chi Ho Ricky; Hockley, Joseph Allan; Garbowski, Marek Waldemar; Ferguson, John M.; Samuelson, Shaun D.; Jansen, Shirley JaneThis report presents 3 procedures with visceral chimney stenting in conjunction with an endovascular aneurysm sealing (EVAS) device, known as chEVAS, for treatment of type 1a endoleak. It includes the first published chEVAS in a patient with previous fenestrated endovascular aneurysm repair (FEVAR). Cases include an 80-year-old man 8 years after FEVAR for a juxtarenal abdominal aortic aneurysm (AAA); an 85-year-old woman 9 months after endovascular aneurysm repair (EVAR) for a ruptured infrarenal AAA; and an 84-year-old woman 3 months after EVAR for a symptomatic infrarenal AAA. Technical success was achieved in all cases, with 1 postoperative death. The remaining 2 patients had no residual type 1a endoleak at 10 and 14 months respectively. 2017
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Mithieux, Suzanne M.; Aghaei-Ghareh-Bolagh, Behnaz; Yan, Leping; Kuppan, Kekini V.; Wang, Yiwei; Garces-Suarez, Francia; Li, Zhe; Maitz, Peter K.M.; Carter, Elizabeth A.; Limantoro, Christina; Chrzanowski, Wojciech; Cookson, David J.; Riboldi-Tunnicliffe, Alan; Baldock, Clair; Ohgo, Kosuke; Kumashiro, Kristin K.; Edwards, Glenn Anthony; Weiss, Anthony StevenA novel, pure, synthetic material is presented that promotes the repair of full-thickness skin wounds. The active component is tropoelastin and leverages its ability to promote new blood vessel formation and its cell recruiting properties to accelerate wound repair. Key to the technology is the use of a novel heat-based, stabilized form of human tropoelastin which allows for tunable resorption. This implantable material contributes a tailored insert that can be shaped to the wound bed, where it hydrates to form a conformable protein hydrogel. Significant benefits in the extent of wound healing, dermal repair, and regeneration of mature epithelium in healthy pigs are demonstrated. The implant is compatible with initial co-treatment with full- and split-thickness skin grafts. The implant's superiority to sterile bandaging, commercial hydrogel and dermal regeneration template products is shown. On this basis, a new concept for a prefabricated tissue repair material for point-of-care treatment of open wounds is provided. 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Martez, Gonzalo J.; Celermajer, David S.; Patel, Sanjay[No abstract available]
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Kim, Seung Jae; Fong, Angelina Y.; Pilowsky, Paul M.; Abbott, Stephen B.G.Key points: In anaesthetized rats, acute intermittent hypoxia increases sympathetic nerve activity, sympathetic peripheral chemoreflex sensitivity and central sympatheticrespiratory coupling. Reninangiotensin system inhibition prevents the sympathetic effects of intermittent hypoxia, with intermittent injections of angiotensin II into the systemic circulation replicating these effects. Bilateral carotid body denervation reduces the sympathetic effects of acute intermittent hypoxia and eliminates the increases in chemoreflex sensitivity and sympatheticrespiratory coupling. Pharmacological inhibition of the subfornical organ also reduces the sympathetic effects of acute intermittent hypoxia, although it has no effect on the increases in chemoreflex sensitivity and central sympatheticrespiratory coupling. Combining both interventions eliminates the sympathetic effects of both intermittent hypoxia and angiotensin II. Abstract: Circulating angiotensin II (AngII) is vital for arterial pressure elevation following intermittent hypoxia in rats, although its importance in the induction of sympathetic changes is unclear. We tested the contribution of the reninangiotensin system to the effects of acute intermittent hypoxia (AIH) in anaesthetized and ventilated rats. There was a 33.72.9% increase in sympathetic nerve activity (SNA), while sympathetic chemoreflex sensitivity and central sympatheticrespiratory coupling increased by one-fold following AIH. The sympathetic effects of AIH were prevented by blocking angiotensin type 1 receptors with systemic losartan. Intermittent systemic injections of AngII (Int.AngII) elicited similar sympathetic responses to AIH. To identify the neural pathways responsible for the effects of AIH and Int.AngII, we performed bilateral carotid body denervation, which reduced the increase in SNA by 56% and 45%, respectively. Conversely, pharmacological inhibition of the subfornical organ (SFO), an established target of circulating AngII, reduced the increase in SNA following AIH and Int.AngII by 65% and 59%, respectively, although it did not prevent the sensitization of the sympathetic peripheral chemoreflex, nor the increase in central sympatheticrespiratory coupling. Combined carotid body denervation and inhibition of the SFO eliminated the enhancement of SNA following AIH and Int.AngII. Repeated systemic injections of phenylephrine caused an elevation in SNA similar to AIH, and this effect was prevented by a renin inhibitor, aliskiren. Our findings show that the sympathetic effects of AIH are the result of RAS-mediated activations of the carotid bodies and the SFO. 2018 The Authors. The Journal of Physiology 2018 The Physiological Society
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Cannizzo, Carla M.; Adonopulos, Aaron A.; Solly, Emma L.; Ridiandries, Anisyah; Vanags, Laura Z.; Mulangala, Jocelyne; Yuen, Sui Ching G.; Tsatralis, Tania; Henriquez, Rodney; Robertson, Stacy; Nicholls, Stephen J.; Di Bartolo, Belinda Ann; Ng, Martin K.C.; Ting Lam, Yuen; Bursill, C. A.; Tan, Joanne Tsui MingHigh-density lipoproteins augment hypoxia-induced angiogenesis by inducing the key angiogenic vascular endothelial growth factor A (VEGFA) and total protein levels of its receptor 2 (VEGFR2). The activation/ phosphorylation of VEGFR2 is critical formediating downstream, angiogenic signaling events. This study aimed to determine whether reconstituted high-density lipoprotein (rHDL) activates VEGFR2 phosphorylation and the downstream signaling events and the importance of VEGFR2 in the proangiogenic effects of rHDL in hypoxia. In vitro, rHDL increased VEGFR2 activation and enhanced phosphorylation of downstream, angiogenic signaling proteins ERK1/2 and p38 MAPK in hypoxia. Incubation with a VEGFR2-neutralizing antibody attenuated rHDLinduced phosphorylation of VEGFR2, ERK1/2, p38MAPK, and tubule formation. In a murine model of ischemiadriven neovascularization, rHDL infusions enhanced blood perfusion and augmented capillary and arteriolar density. Infusion of a VEGFR2-neutralizing antibody ablated those proangiogenic effects of rHDL. Circulating Sca1+/CXCR4+angiogenic progenitor cell levels, important for neovascularization in response to ischemia, were higher in rHDL-infused mice 3 d after ischemic induction, but that did not occur in mice that also received the VEGFR2-neutralizing antibody. In summary, VEGFR2 has a key role in the proangiogenic effects of rHDL in hypoxia/ischemia. These findings have therapeutic implications for angiogenic diseases associated with an impaired response to tissue ischemia. FASEB.
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Wong, Nathan K.P.; Nicholls, Stephen J.; Tan, Joanne Tsui Ming; Bursill, C. A.Almost 600 million people are predicted to have diabetes mellitus (DM) by 2035. Diabetic patients suffer from increased rates of microvascular and macrovascular complications, associated with dyslipidaemia, impaired angiogenic responses to ischaemia, accelerated atherosclerosis, and inflammation. Despite recent treatment advances, many diabetic patients remain refractory to current approaches, highlighting the need for alternative agents. There is emerging evidence that high-density lipoproteins (HDL) are able to rescue diabetes-related vascular complications through diverse mechanisms. Such protective functions of HDL, however, can be rendered dysfunctional within the pathological milieu of DM, triggering the development of vascular complications. HDL-modifying therapies remain controversial as many have had limited benefits on cardiovascular risk, although more recent trials are showing promise. This review will discuss the latest data from epidemiological, clinical, and pre-clinical studies demonstrating various roles for HDL in diabetes and its vascular complications that have the potential to facilitate its successful translation. 2018 by the authors. Licensee MDPI, Basel, Switzerland.
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Passam, Freda H.; Chiu, Joyce; Ju, Lining Arnold; Pijning, Aster E.; Jahan, Zeenat; Mor-Cohen, Ronit; Yeheskel, Adva; Kolek, Katra; Thichen, Lena; Aponte-Santamar, Camilo; Grer, Frauke; Hogg, Philip J.How proteins harness mechanical force to control function is a significant biological question. Here we describe a human cell surface receptor that couples ligand binding and force to trigger a chemical event which controls the adhesive properties of the receptor. Our studies of the secreted platelet oxidoreductase, ERp5, have revealed that it mediates release of fibrinogen from activated platelet ?IIb?3 integrin. Protein chemical studies show that ligand binding to extended ?IIb?3 integrin renders the ?I-domain Cys177-Cys184 disulfide bond cleavable by ERp5. Fluid shear and force spectroscopy assays indicate that disulfide cleavage is enhanced by mechanical force. Cell adhesion assays and molecular dynamics simulations demonstrate that cleavage of the disulfide induces long-range allosteric effects within the ?I-domain, mainly affecting the metal-binding sites, that results in release of fibrinogen. This coupling of ligand binding, force and redox events to control cell adhesion may be employed to regulate other protein-protein interactions. Passam et al.
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Wong, Nathan K.P.; Cheung, Helena; Solly, Emma L.; Vanags, Laura Z.; Ritchie, William A.; Nicholls, Stephen J.; Ng, Martin K.C.; Bursill, C. A.; Tan, Joanne Tsui MingAngiogenesis, the process of forming new blood vessels, is crucial in the physiological response to ischemia, though it can be detrimental as part of inflammation and tumorigenesis. We have previously shown that high-density lipoproteins (HDL) modulate angiogenesis in a context-specific manner via distinct classical signalling pathways, enhancing hypoxia-induced angiogenesis while suppressing inflammatory-driven angiogenesis. Whether additional novel targets exist to account for these effects are unknown. A microarray approach identified two novel genes, cyclic-adenosine-monophosphate-response-element-binding protein 3 regulatory factor (CREBRF) and tripartite motif-containing protein 2 (TRIM2) that were upregulated by reconstituted HDL (rHDL). We measured CREBRF and TRIM2 expression in human coronary artery endothelial cells following incubation with rHDL and exposure to either hypoxia or an inflammatory stimulus. We found that CREBRF and TRIM2 mRNA were significantly upregulated by rHDL, particularly in response to its phospholipid component 1-palmitoyl-2-linoleoyl-phosphatidylcholine, however, protein expression was not significantly altered. Knockdown of TRIM2 impaired endothelial cell tubulogenesis in vitro in both hypoxia and inflammation, implying a necessary role in angiogenesis. Furthermore, TRIM2 knockdown attenuated rHDL-induced tubule formation in hypoxia, suggesting that it is important in mediating the pro-angiogenic action of rHDL. Our study has implications for understanding the regulation of angiogenesis in both of these pathophysiological contexts by HDL. 2018 by the authors. Licensee MDPI, Basel, Switzerland.
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Pleines, Irina; Lebois, Marion; Gangatirkar, Pradnya; Au, Amanda E.; Lane, Rachael M.; Henley, Katya J.; Kauppi, Maria; Corbin, Jason E.; Cannon, Ping Zhi Fang; Bernardini, Jonathan P.; Alwis, Imala D.; Jarman, Kate E.; Ellis, Sarah L.; Metcalf, Donald; Jackson, Shaun P.; Schoenwaelder, Simone M.; Kile, Benjamin T.; Josefsson, Emma C.The circulating life span of blood platelets is regulated by the prosurvival protein BCL-X<inf>L</inf>. It restrains the activity of BAK and BAX, the essential prodeath mediators of intrinsic apoptosis. Disabling the platelet intrinsic apoptotic pathway in mice by deleting BAK and BAX results in a doubling of platelet life span and concomitant thrombocytosis. Apoptotic platelets expose phosphatidylserine (PS) via a mechanism that is distinct from that driven by classical agonists. Whether there is any role for apoptotic PS in platelet function in vivo, however, is unclear. Apoptosis has also been associated with the platelet storage lesion (PSL), the constellation of biochemical deteriorations that occur during blood bank storage. In this study, we investigated the role of BAK/BAX-mediated apoptosis in hemostasis and thrombosis and in the development of the PSL. We show that although intrinsic apoptosis is rapidly induced during storage at 37C, it is not detected when platelets are kept at the standard storage temperature of 22C. Remarkably, loss of BAK and BAX did not prevent the development of the PSL at either temperature. BAK/BAX-deficient mice exhibited increased bleeding times and unstable thrombus formation. This phenotype was not caused by impaired PS exposure, but was associated with a defect in granule release from aged platelets. Strikingly, rejuvenation of BAK/BAX-deficient platelets in vivo completely rescued the observed hemostatic defects. Thus, apoptotic culling of old platelets from the bloodstream is essential to maintain a functional, hemostatically reactive platelet population. Inhibiting intrinsic apoptosis in blood banked platelets is unlikely to yield significant benefit. 2018 by The American Society of Hematology
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Clayton, Zoe E.; Tan, Richard P.; Miravet, Maria M.; Lennartsson, Katarina; Cooke, John P.; Bursill, C. A.; Wise, Steven G.; Patel, SanjayChronic wounds are a major complication in patients with cardiovascular diseases. Cell therapies have shown potential to stimulate wound healing, but clinical trials using adult stem cells have been tempered by limited numbers of cells and invasive procurement procedures. Induced pluripotent stem cells (iPSCs) have several advantages of other cell types, for example they can be generated in abundance from patients somatic cells (autologous) or those from a matched donor. iPSCs can be efficiently differentiated to functional endothelial cells (iPSC-ECs). Here, we used a murine excisional wound model to test the pro-angiogenic properties of iPSC-ECs in wound healing. Two full-thickness wounds were made on the dorsum of NOD-SCID mice and splinted. iPSC-ECs (5 10 5 ) were topically applied to one wound, with the other serving as a control. Treatment with iPSC-ECs significantly increased wound perfusion and accelerated wound closure. Expression of endothelial cell (EC) surface marker, platelet endothelial cell adhesion molecule (PECAM-1) (CD31), and pro-angiogenic EC receptor, Tie1, mRNA was up-regulated in iPSC-EC treated wounds at 7 days post-wounding. Histological analysis of wound sections showed increased capillary density in iPSC-EC wounds at days 7 and 14 post-wounding, and increased collagen content at day 14. Anti-GFP fluorescence confirmed presence of iPSC-ECs in the wounds. Bioluminescent imaging (BLI) showed progressive decline of iPSC-ECs over time, suggesting that iPSC-ECs are acting primarily through short-term paracrine effects. These results highlight the pro-regenerative effects of iPSC-ECs and demonstrate that they are a promising potential therapy for intractable wounds. 2018 The Author(s).
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Roy, Arijit; Farnham, M. M. J.; Derakhshan, Fatemeh N.; Pilowsky, Paul M.; Wilson, Richard J.A.Key points: Activity-dependent plasticity can be induced in carotid body (CB) chemosensory afferents without chronic intermittent hypoxia (CIH) preconditioning by acute intermittent hypoxia coincident with bouts of hypercapnia (AIH-Hc). Several properties of this acute plasticity are shared with CIH-dependent sensory long-term facilitation (LTF) in that induction is dependent on 5-HT, angiotensin II, protein kinase C and reactive oxygen species. Several properties differ from CIH-dependent sensory LTF; H<inf>2</inf>O<inf>2</inf> appears to play no part in induction, whereas maintenance requires purinergic P2X2/3 receptor activation and is dependent on transient receptor potential vanilloid type 1 (TRPV1) receptor sensitization. Because P2X2/3 and TRPV1 receptors are located in carotid sinus nerve (CSN) terminals but not presynaptic glomus cells, a primary site of the acute AIH-Hc induced sensory LTF appears to be postsynaptic. Our results obtained in vivo suggest a role for TRPV1-dependent CB activity in acute sympathetic LTF. We propose that P2X-TRPV1-receptor-dependent sensory LTF may constitute an important early mechanism linking sleep apnoea with hypertension and/or cardiovascular disease. Abstract: Apnoeas constitute an acute existential threat to neonates and adults. In large part, this threat is detected by the carotid bodies, which are the primary peripheral chemoreceptors, and is combatted by arousal and acute cardiorespiratory responses, including increased sympathetic output. Similar responses occur with repeated apnoeas but they continue beyond the last apnoea and can persist for hours [i.e. ventilatory and sympathetic long-term facilitation (LTF)]. These long-term effects may be adaptive during acute episodic apnoea, although they may prolong hypertension causing chronic cardiovascular impairment. We report a novel mechanism of acute carotid body (CB) plasticity (sensory LTF) induced by repeated apnoea-like stimuli [i.e. acute intermittent hypoxia coincident with bouts of hypercapnia (AIH-Hc)]. This plasticity did not require chronic intermittent hypoxia preconditioning, was dependent on P2X receptors and protein kinase C, and involved heat-sensitive transient receptor potential vanilloid type 1 (TRPV1) receptors. Reactive oxygen species (O<inf>2</inf>) were involved in initiating plasticity only; no evidence was found for H<inf>2</inf>O<inf>2</inf> involvement. Angiotensin II and 5-HT receptor antagonists, losartan and ketanserin, severely reduced CB responses to individual hypoxic-hypercapnic challenges and prevented the induction of sensory LTF but, if applied after AIH-Hc, failed to reduce plasticity-associated activity. Conversely, TRPV1 receptor antagonism had no effect on responses to individual hypoxic-hypercapnic challenges but reduced plasticity-associated activity by ?50%. Further, TRPV1 receptor antagonism in vivo reduced sympathetic LTF caused by AIH-Hc, although only if the CBs were functional. These data demonstrate a new mechanism of CB plasticity and suggest P2X-TRPV1-dependent sensory LTF as a novel target for pharmacological intervention in some forms of neurogenic hypertension associated with recurrent apnoeas. 2017 The Authors. The Journal of Physiology 2017 The Physiological Society
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Bautista, Tara G.; Fong, Angelina Y.; Pilowsky, Paul M.; Ikeda, Keiko; Kawakami, Kiyoshi; Spirovski, Darko; Onimaru, HiroshiThe inhibitory peptide galanin is expressed within the retrotrapezoidal nucleus (RTN) a key central chemoreceptor site that also contains the active expiratory oscillator. It was previously reported that microinjection of galanin into pre-Bzinger complex containing the inspiratory oscillator exerts inhibitory effects on inspiratory motor output and respiratory rhythm. In neonatal rats, the present study aimed to investigate: (1) expression of galanin within the parafacial respiratory group (pFRG), which overlaps anatomically and functionally with the adult RTN, and; (2) effects of galanin on respiratory rhythm using the in vitro brainstem-spinal cord preparation. We showed that 14 2% of Phox2b-immunoreactive (ir) neurons in the parafacial region were also galanin-ir. Galanin peptide expression was confirmed within 3/9 CO<inf>2</inf>-sensitive, Phox2b-ir Pre-Inspiratory neurons (Pre-I) recorded in parafacial region. Bath application of galanin (0.10.2 M): (1) decreased the duration of membrane depolarization in both Pre-I and inspiratory pFRG neurons, and; (2) decreased the number of C4 bursts that were associated with each burst in Pre-I neurons within the pFRG. In preparations showing episodic breathing at baseline, the respiratory patterning reverted to the normal pattern of single, uniformly rhythmic C4 bursts (n = 10). In preparations with normal respiratory patterning at baseline, slowing of C4 rhythm (n = 7) resulted although rhythmic bursting in recorded Pre-I neurons remained unperturbed (n = 6). This study therefore demonstrates that galanin is expressed within the pFRG of neonatal rats, including neurons that are intrinsically chemosensitive. Overall the peptide has an inhibitory effect on inspiratory motor output, as previously shown in adults. 2018 IBRO
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Ooi, Esther M.; Ellis, Katrina L.; Barrett, Hugh Hugh R.; Watts, Gerald F.; Hung, Joseph C.; Beilby, John P.; Thompson, Peter Lindsay; Stobie, Paul; McQuillan, Brendan M.Background and aims: Lipoprotein(a) [Lp(a)] is an emerging genetic risk factor for cardiovascular disease (CVD). We examined whether plasma Lp(a) concentration and apolipoprotein(a) [apo(a)] isoform size are associated with extent and severity of coronary artery disease (CAD), and the presence of carotid artery plaque. Methods: We included in our study male participants (n = 263) from a cohort with angiographically defined premature CAD (Carotid Ultrasound in Patients with Ischemic Heart Disease). The angiographic extent and severity of CAD were determined by the modified Gensini and Coronary Artery Stenosis?20% (CAGE) scores. Carotid artery plaque was assessed by bilateral carotid B-mode ultrasound. Apo(a) isoform size was determined by LPA Kringle IV-2 copy number (KIV-2 CN). Results: Lp(a) concentration, but not KIV-2 CN, was positively associated with the Gensini score. The association remained significant following adjustment for conventional CVD risk factors (all p < 0.05). Lp(a) concentration and elevated Lp(a) [?50 mg/dL] were positively associated with the CAGE?20 score, independent of conventional CVD risk factors. KIV-2 C N Q1 (lowest KIV-2 CN quartile) was associated with CAGE?20 score and KIV-2 CN, with the CAGE?20 score in those without diabetes. In multivariate models that included phenotypic familial hypercholesterolemia or low-density lipoprotein cholesterol, Lp(a) concentration, but not KIV-2 CN, was independently associated with the Gensini and CAGE?20 scores. No significant associations between Lp(a) concentration and KIV-2 CN with carotid artery plaque were observed. Conclusions: Lp(a) concentration, but not apo(a) isoform size, is independently associated with angiographic extent and severity of CAD. Neither Lp(a) nor apo(a) isoform size is associated with carotid artery plaque. 2018
