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https://www.readbyqxmd.com/read/28087362/clinical-phenotypes-and-outcomes-of-heritable-and-sporadic-pulmonary-veno-occlusive-disease-a-population-based-study
#1
David Montani, Barbara Girerd, Xavier Jaïs, Marilyne Levy, David Amar, Laurent Savale, Peter Dorfmüller, Andrei Seferian, Edmund M Lau, Mélanie Eyries, Jérôme Le Pavec, Florence Parent, Damien Bonnet, Florent Soubrier, Elie Fadel, Olivier Sitbon, Gérald Simonneau, Marc Humbert
BACKGROUND: Bi-allelic mutations of the EIF2AK4 gene cause heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH). We aimed to assess the effect of EIF2AK4 mutations on the clinical phenotypes and outcomes of PVOD/PCH. METHODS: We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network. We reviewed the clinical data and outcomes from all patients referred to the French Referral Centre (Pulmonary Department, Hospital Kremlin-Bicêtre, University Paris-Sud) with either confirmed or highly probable PVOD/PCH with DNA available for mutation screening (excluding patients with other risk factors of pulmonary hypertension, such as chronic respiratory diseases)...
January 10, 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28072560/a-prostacyclin-analog-cicaprost-exhibits-potent-anti-inflammatory-activity-in-human-primary-immune-cells-and-a-uveitis-model
#2
Jenny W Wang, Chau Vu, Neil J Poloso
PURPOSE: To investigate the therapeutic potential of a prostacyclin (IP) receptor agonist for ocular inflammation and the effect on immune cells. METHODS: The anti-inflammatory activities of cicaprost were determined in primary human monocyte-derived macrophages and human monocyte-derived dendritic cells (MoDC), as well as a lipopolysaccharides (LPS)-induced rat uveitis model. Multiple cytokine release was measured by utilizing Luminex Technology. Prostacyclin (IP) Receptor expression was detected by reverse transcription-polymerase chain receptor...
January 10, 2017: Journal of Ocular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28072531/discovery-of-2-1r-4r-4-4-chlorophenyl-phenyl-carbamoyl-oxy-methyl-cyclohexyl-methoxy-acetate-ralinepag-an-orally-active-prostacyclin-receptor-agonist-for-the-treatment-of-pulmonary-arterial-hypertension
#3
Thuy-Anh Tran, Bryan Kramer, Young-Jun Shin, Pureza Vallar, P Douglas Boatman, Ning Zou, Carleton R Sage, Tawfik Gharbaoui, Ashwin Krishnan, Biman Pal, Sagar R Shakya, Antonio Garrido Montalban, John Wesley Adams, Juan Ramirez, Dominic Peter Behan, Anna Shifrina, Anthony Blackburn, Tina Leakakos, Yunqing Shi, Michael Morgan, Abu Sadeque, Weichao Chen, David John Unett, Ibragim Gaidarov, Xiaohua Chen, Steve Chang, Hsin-Hui Shu, Shiu-Feng Tung, Graeme Semple
The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) is described. Detailed profiling of a number of analogues resulted in the identification of 3c (APD811, Ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family, and a more modest 40- 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are superior in vitro to MRE269 (the active metabolite of the clinical compound NS-304) in multiple in vitro measures of IP receptor mediated cAMP signaling...
January 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28067100/effects-of-a-single-bout-of-strenuous-exercise-on-platelet-activation-in-female-apoe-ldlr-mice
#4
K Przyborowski, H Kassassir, M Wojewoda, K Kmiecik, B Sitek, K Siewiera, A Zakrzewska, A M Rudolf, R Kostogrys, C Watala, J A Zoladz, S Chlopicki
Strenuous physical exercise leads to platelet activation that is normally counterbalanced by the production of endothelium-derived anti-platelet mediators, including prostacyclin (PGI2) and nitric oxide (NO). However, in the case of endothelial dysfunction, e.g. in atherosclerosis, there exists an increased risk for intravascular thrombosis during exercise that might be due to an impairment in endothelial anti-platelet mechanisms. In the present work, we evaluated platelet activation at rest and following a single bout of strenuous treadmill exercise in female ApoE/LDLR(-)(/-) mice with early (3-month-old) and advanced (7-month-old) atherosclerosis compared to female age-matched WT mice...
January 9, 2017: Platelets
https://www.readbyqxmd.com/read/28060719/temporal-quantitative-phosphoproteomics-of-adp-stimulation-reveals-novel-central-nodes-in-platelet-activation-and-inhibition
#5
Florian Beck, Jörg Geiger, Stepan Gambaryan, Fiorella A Solari, Margherita Dell'Aica, Stefan Loroch, Nadine Mattheij, Igor Mindukshev, Oliver Pötz, Kerstin Jurk, Julia M Burkhart, Christian Fufezan, Johan W M Heemskerk, Ulrich Walter, René P Zahedi, Albert Sickmann
ADP enhances platelet activation by virtually any other stimulant to complete aggregation. It binds specifically to the G-protein coupled membrane receptors P2Y1 and P2Y12, stimulating intracellular signaling cascades leading to integrin αIIbβ3 activation, a process that is antagonized by endothelial prostacyclin. P2Y12 inhibitors are among the most successful anti-platelet drugs, however, show remarkable variability in efficacy. We reasoned whether a more detailed molecular understanding of ADP-induced protein phosphorylation could identify (i) critical hubs in platelet signaling towards aggregation, and (ii) novel molecular targets for anti-platelet treatment strategies...
November 9, 2016: Blood
https://www.readbyqxmd.com/read/28050885/results-of-an-international-postmarketing-surveillance-study-of-pl-vegf165-safety-and-efficacy-in-210-patients-with-peripheral-arterial-disease
#6
Roman Deev, Igor Plaksa, Ilia Bozo, Artur Isaev
INTRODUCTION: The effective treatment of chronic lower limb ischemia is one of the most challenging issues confronting vascular surgeons. Current pharmacological therapies play an auxiliary role and cannot prevent disease progression, and new treatment methods are needed. pl-VEGF165, a gene therapy drug, was approved in Russia for the treatment of atherosclerotic peripheral arterial disease (PAD) after clinical studies in 2011. The study drug is an original gene construction in which pl-VEGF165 1...
January 3, 2017: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
https://www.readbyqxmd.com/read/28049123/-recent-advances-in-targeting-the-prostacyclin-pathway-in-pulmonary-arterial-hypertension-irene-m-lang-sean-p-gaine-eur-respir-rev-2015-24-630-641
#7
(no author information available yet)
No abstract text is available yet for this article.
January 2017: European Respiratory Review: An Official Journal of the European Respiratory Society
https://www.readbyqxmd.com/read/28044409/macro-and-microvascular-endothelial-dysfunction-in-diabetes
#8
REVIEW
Yi Shi, Paul M Vanhoutte
Endothelial cells, as well as their major products nitric oxide and prostacyclin, play a key role in the regulation of vascular homeostasis. Diabetes mellitus is an important risk factor for cardiovascular disease. Diabetes-induced endothelial dysfunction is a critical and initiating factor in the genesis of diabetic vascular complications. The present review focuses on both large blood vessels and the microvasculature. The endothelial dysfunction in diabetic macrovascular complications is characterized by a reduced nitric oxide bioavailability, poorly compensated for by increased production of prostacyclin and/or endothelium-dependent hyperpolarizations, and increased production /action of endothelium-derived vasoconstrictors...
January 3, 2017: Journal of Diabetes
https://www.readbyqxmd.com/read/28031017/nitric-oxide-signaling-and-the-cross-talk-with-prostanoids-pathways-in-vascular-system
#9
Bruno R Silva, Tiago D Paula, Michele Paulo, Lusiane M Bendhack
BACKGROUND: This review provides an overview of the cellular signaling of nitric oxide (NO) and prostanoids in vascular cells and the possible cross talk between their pathways, mainly in hypertension, since the imbalance of these two systems has been attributed to development of some cardiovascular diseases. It also deals with the modulation of vasodilation induced by NO donors. NO is a well-known second messenger involved in many cellular functions. CONCLUSION: In the vascular system, the NO produced by endothelial NO-synthase (eNOS) or released by NO donors acts in vascular smooth muscle cells, the binding of NO to Fe2+-heme of soluble guanylyl-cyclase (sGC) activates sGC and the production of cyclic guanosine-3-5-monophosphate (cGMP)...
December 28, 2016: Medicinal Chemistry
https://www.readbyqxmd.com/read/28013348/calpain-1-cleaves-and-inactivates-prostacyclin-synthase-in-mesenteric-arteries-from-diabetic-mice
#10
Voahanginirina Randriamboavonjy, Anastasia Kyselova, Amro Elgheznawy, Sven Zukunft, Ilka Wittig, Ingrid Fleming
Diabetes is associated with a number of co-morbidities including an increased risk of developing cardiovascular diseases. The activation of Ca(2+)-activated proteases of the calpain family has been implicated in platelet activation associated with diabetes and this study aimed to determine the role of calpain activation in the development of endothelial dysfunction. Diabetes induction in mice attenuated acetylcholine-induced relaxation of mesenteric artery rings, an effect prevented in mice receiving a calpain inhibitor...
January 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/27995364/transition-in-the-mechanism-of-flow-mediated-dilation-with-aging-and-development-of-coronary-artery-disease
#11
Andreas M Beyer, Natalya Zinkevich, Bradley Miller, Yanping Liu, April L Wittenburg, Michael Mitchell, Ralph Galdieri, Andrey Sorokin, David D Gutterman
In microvessels of patients with coronary artery disease (CAD), flow-mediated dilation (FMD) is largely dependent upon the endothelium-derived hyperpolarizing factor H2O2. The goal of this study is to examine the influence of age and presence or absence of disease on the mechanism of FMD. Human coronary or adipose arterioles (~150 µm diameter) were prepared for videomicroscopy. The effect of inhibiting COX [indomethacin (Indo) or NOS (L-NAME), eliminating H2O2 (polyethylene glycol-catalase (PEG-CAT)] or targeting a reduction in mitochondrial ROS with scavengers/inhibitors [Vitamin E (mtVitamin E); phenylboronic acid (mtPBA)] was determined in children aged 0-18 years; young adults 19-55 years; older adults >55 years without CAD, and similarly aged adults with CAD...
January 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/27988834/selexipag-a-review-in-pulmonary-arterial-hypertension
#12
Sean T Duggan, Susan J Keam, Celeste B Burness
Selexipag (Uptravi(®)) is an orally active, first-in-class, selective prostacyclin IP receptor agonist. Selexipag was approved recently in the EU for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients with WHO functional class (FC) II or III as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist and/or a phosphodiesterase type 5 inhibitor or as monotherapy in patients who are not candidates for these therapies, and in the USA for the treatment of PAH (WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH...
December 17, 2016: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
https://www.readbyqxmd.com/read/27965959/a-novel-antithrombotic-mechanism-mediated-by-the-receptors-of-the-kallikrein-kinin-and-renin-angiotensin-systems
#13
REVIEW
Alvin H Schmaier
The contact activation (CAS) and kallikrein/kinin (KKS) systems regulate thrombosis risk in two ways. First, the CAS influences contact activation-induced factor XI activation and thrombin formation through the hemostatic cascade. Second, prekallikrein (PK) and bradykinin of the KKS regulate expression of three vessel wall G-protein-coupled receptors, the bradykinin B2 receptor (B2R), angiotensin receptor 2, and Mas to influence prostacyclin formation. The degree of intravascular prostacyclin formation inversely regulates intravascular thrombosis risk...
2016: Frontiers in Medicine
https://www.readbyqxmd.com/read/27956919/cardiovascular-effects-of-the-essential-oil-of-croton-argyrophylloides-in-normotensive-rats-role-of-the-autonomic-nervous-system
#14
Thayane Rebeca Alves-Santos, Rodrigo José Bezerra de Siqueira, Gloria Pinto Duarte, Saad Lahlou
Cardiovascular effects of the essential oil of Croton argyrophylloides Muell. Arg. (EOCA) were investigated in normotensive rats. In saline-pretreated anesthetized or conscious rats, intravenous (i.v.) injection of the EOCA induced dose-dependent hypotension. Dose-dependent tachycardia was observed only in conscious rats. In anesthetized rats, cervical bivagotomy failed to enhance EOCA-induced hypotension but unmasked significant bradycardia. In conscious rats, i.v. pretreatment with methylatropine, but not with atenolol or L-NAME, reduced both hypotensive and tachycardiac responses to EOCA...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/27942445/combination-therapy-with-riociquat-and-inhaled-treprostinil-in-inoperable-and-progressive-chronic-thromboembolic-pulmonary-hypertension
#15
John W Swisher, Dillon Elliott
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by formation of chronic, organized thrombus in pulmonary arteries resulting in development of pulmonary hypertension. We describe the favorable recovery of a patient with inoperable CTEPH treated with combination riociguat and inhaled treprostinil. The patient is a 77 year old female who presented with bilateral pulmonary emboli and was anticoagulated with warfarin for six months. One year later the patient developed recurrent dyspnea and multiple bilateral pulmonary emboli were again noted...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/27929408/a-review-of-targeted-pulmonary-arterial-hypertension-specific-pharmacotherapy
#16
REVIEW
Ali Ataya, Jessica Cope, Hassan Alnuaimat
Significant advances in the understanding of the pathophysiology of pulmonary arterial hypertension over the past two decades have led to the development of targeted therapies and improved patient outcomes. Currently, a broad armamentarium of pulmonary arterial hypertension-specific drugs exists to assist in the treatment of this complex disease state. In this manuscript, we provide a comprehensive review of the current Food and Drug Administration (FDA)-approved pulmonary arterial hypertension-specific therapies, and their supporting evidence for adults, targeting the nitric oxide, soluble guanylate cyclase, endothelin, and prostacyclin pathways...
December 6, 2016: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/27926661/the-effect-of-intraoperative-and-6-h-postoperative-intravenous-administration-of-low-dose-prostacyclin-on-the-endothelium-hemostasis-and-hemodynamics-in-patients-undergoing-a-pancreaticoduodenoctemy-a-randomized-controlled-pilot-study
#17
Pär I Johansson, Christian R Mortensen, Tatiana Nielsen, Carsten Tollund, Jakob Stensballe, Carsten P Hansen, Hans J Frederiksen, Sisse R Ostrowski
BACKGROUND: Capillary leakage, secondary to endothelial breakdown, is common in patients undergoing major surgical procedures with extensive tissue injury and this is associated with increased morbidity and mortality. Prostacyclin has been ascribed cytoprotective properties together with its vasodilatory and antiplatelet effects. The present pilot study investigated the safety and endothelial protective effects of low-dose prostacyclin infusion. PATIENTS AND METHODS: A randomized placebo-controlled pilot study evaluating the effect of prostacyclin (iloprost) infusion (1...
December 6, 2016: European Journal of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/27919660/a-comparison-of-vasodilation-mode-among-selexipag-ns-304-2-4-5-6-diphenylpyrazin-2-yl-isopropyl-amino-butoxy-n-methylsulfonyl-acetamide-its-active-metabolite-mre-269-and-various-prostacyclin-receptor-agonists-in-rat-porcine-and-human-pulmonary-arteries
#18
Chiaki Fuchikami, Kohji Murakami, Koyuki Tajima, Junko Homan, Keiji Kosugi, Kazuya Kuramoto, Michiko Oka, Keiichi Kuwano
Selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N- (methylsulfonyl)acetamide]) is a novel, orally available non-prostanoid prostacyclin receptor (IP receptor) agonist that has recently been approved for the treatment of pulmonary arterial hypertension (PAH). We examined the effect of the active metabolite of selexipag, MRE-269, and IP receptor agonists that are currently available as PAH therapeutic drugs on the relaxation of rat, porcine and human pulmonary artery. cAMP formation in human pulmonary artery smooth muscle cells was induced by all test compounds (MRE-269, epoprostenol, iloprost, treprostinil and beraprost sodium) and suppressed by IP receptor antagonists (CAY10441 and 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid)...
December 3, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27916240/spatial-phenotyping-of-the-endocardial-endothelium-as-a-function-of-intracardiac-hemodynamic-shear-stress
#19
Margaret E McCormick, Elisabetta Manduchi, Walter R T Witschey, Robert C Gorman, Joseph H Gorman, Yi-Zhou Jiang, Christian J Stoeckert, Alex J Barker, Samuel Yoon, Michael Markl, Peter F Davies
Despite substantial evidence for the central role of hemodynamic shear stress in the functional integrity of vascular endothelial cells, hemodynamic and molecular regulation of the endocardial endothelium lining the heart chambers remains understudied. We propose that regional differences in intracardiac hemodynamics influence differential endocardial gene expression leading to phenotypic heterogeneity of this cell layer. Measurement of intracardiac hemodynamics was performed using 4-dimensional flow MRI in healthy humans (n=8) and pigs (n=5)...
January 4, 2017: Journal of Biomechanics
https://www.readbyqxmd.com/read/27916219/coupling-factor-6-is-upregulated-in-monocrotaline-induced-pulmonary-arterial-hypertension-in-rats
#20
Nannan Li, Jie Yin, Weidong Cai, Jingjing Liu, Na Zhang, Suhua Yan, Lucheng Song, Xiaolu Li
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare and fatal disease. The prostacyclin (PGI2) pathway is a well-known therapeutic target for PAH. As a novel vasoconstrictive peptide, coupling factor 6 (CF6) has been recognized as the only endogenous inhibitor of PGI2. However, the relationship between CF6 and PAH is still unknown. In this study, we investigated the involvement of CF6 in PAH in rats. METHODS: A total of 80 Sprague-Dawley rats were randomly divided into 2 groups: a control group (with saline intraperitoneally) and a monocrotaline (MCT)-treated group (with MCT 60mg/kg intraperitoneal injection)...
December 2016: American Journal of the Medical Sciences
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