title: Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis without increased bleeding risk.
abstract: Atrial fibrillation (AF) is a major risk factor for cardio-embolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern. This study sought to identify new targets to develop safer antithrombotic therapies.
  
  
  
  Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke brought to light a stroke-related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was down-regulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. Remarkably, the tail bleeding time was unchanged. Accordingly, both TRC051384 and tubastatin A, i.e. two Hsp70 inducers via different pathways, delayed thrombus formation in WT mice, the tail bleeding time still being unaltered. Most interestingly, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression and higher circulating levels of activated protein C upon thrombotic stimulus.
  
  
  
  Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, and is especially promising for treating AF patients and in other situations where there is also a major bleeding hazard.
authors.affiliation: Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Center for Applied Medical Research (CIMA), IdiSNA, Navarra's Health Research Institute, University of Navarra, Pío XII, 55, Pamplona, Spain.
authors.forename: Mikel
authors.initials: M
authors.lastname: Allende
authors.affiliation: Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Center for Applied Medical Research (CIMA), IdiSNA, Navarra's Health Research Institute, University of Navarra, Pío XII, 55, Pamplona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Molina
authors.affiliation: Proteomics, Genomics & Bioinformatics Unit, Center for Applied Medical Research (CIMA), IdiSNA, Navarra's Health Research Institute, University of Navarra, Pamplona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Guruceaga
authors.affiliation: Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Center for Applied Medical Research (CIMA), IdiSNA, Navarra's Health Research Institute, University of Navarra, Pío XII, 55, Pamplona, Spain.
authors.forename: Ibai
authors.initials: I
authors.lastname: Tamayo
authors.affiliation: Department of Haematology, IBSAL-Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: José Ramón
authors.initials: JR
authors.lastname: González-Porras
authors.affiliation: Servicio de Hematología, Hospital Universitario de Burgos, Burgos, Spain.
authors.forename: Tomás José
authors.initials: TJ
authors.lastname: Gonzalez-López
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, IdiSNA, Navarra's Health Research Institute, University of Navarra, Pamplona, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Toledo
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), IdiSNA, Navarra's Health Research Institute, University of Navarra, Pamplona, Spain.
authors.forename: Obdulia
authors.initials: O
authors.lastname: Rabal
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), IdiSNA, Navarra's Health Research Institute, University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ugarte
authors.affiliation: Centro Regional de Hemodonación, Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Roldán
authors.affiliation: Centro Regional de Hemodonación, Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Rivera
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), IdiSNA, Navarra's Health Research Institute, University of Navarra, Pamplona, Spain.
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
authors.affiliation: Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Center for Applied Medical Research (CIMA), IdiSNA, Navarra's Health Research Institute, University of Navarra, Pío XII, 55, Pamplona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Montes
authors.affiliation: Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Center for Applied Medical Research (CIMA), IdiSNA, Navarra's Health Research Institute, University of Navarra, Pío XII, 55, Pamplona, Spain jhermida@unav.es.
authors.forename: José
authors.initials: J
authors.lastname: Hermida
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism*; D001760:Bleeding Time; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D018840:HSP70 Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011486:Protein C / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012307:Risk Factors; D020521:Stroke / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D018180:Thrombomodulin / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D013997:Time Factors; D015854:Up-Regulation; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C559000:1-(2-(morpholin-4-yl)ethyl)-3-(4-(-3-(6-(morpholin-4-yl)pyridin- 2-yl)prop-2-enoyl)phenyl)urea dihydrochloride; D005343:Fibrinolytic Agents; D018840:HSP70 Heat-Shock Proteins; C525621:HSPA1B protein, human; C498550:Hsp70.3 protein, mouse; D009025:Morpholines; D011486:Protein C; D011725:Pyridines; C569169:THBD protein, mouse; D018180:Thrombomodulin; C081884:heat-shock protein 70.1; D014508:Urea; D001241:Aspirin
keywords: Atrial fibrillation; Bleeding; Hsp70 heat-shock proteins; Stroke; Thrombosis