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Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis with no increased bleeding risk

ABSTRACT: Atrial fibrillation (AF) is a major risk factor for cardioembolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern particularly when antiplatelet treatment is simultaneously administered. Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke identified 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 downregulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out (KO) mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. In WT mice, Hsp70 inducers (TRC051384, or tubastatin A) delayed thrombus formation. Remarkably, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression, higher circulating levels of activated protein C (APC) upon thrombotic stimulus and increased protection against endothelial apoptosis. Thus, Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, being especially promising in situations where there is a major bleeding hazard.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66724 | GEO | 2016/04/01

SECONDARY ACCESSION(S): PRJNA277813

REPOSITORIES: GEO

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Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis with no increased bleeding risk

Project description:Atrial fibrillation (AF) is a major risk factor for cardioembolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern particularly when antiplatelet treatment is simultaneously administered. Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke identified 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 downregulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out (KO) mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. In WT mice, Hsp70 inducers (TRC051384, or tubastatin A) delayed thrombus formation. Remarkably, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression, higher circulating levels of activated protein C (APC) upon thrombotic stimulus and increased protection against endothelial apoptosis. Thus, Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, being especially promising in situations where there is a major bleeding hazard. Microarray analysis in peripheral blood cells includes eight patients with AF and stroke and eight AF subjects without stroke

2016-04-01 | E-GEOD-66724 | biostudies-arrayexpress

INCREASED HEAT SHOCK PROTEIN 70 EXPRESSION BY CM-695 ASSOCIATES WITH STRONG ANTITROMBOTIC EFFECT WITHOUT INCREASING BLEEDING

Project description:BACKGROUND Antithrombotic medications target coagulation factors. Their use is associated with an increased bleeding risk. Safer drugs are needed. We described that the heat shock protein 70 (Hsp70) exhibits antithrombotic properties that do not influence bleeding. OBJECTIVES By using murine models, we want to test the hypothesis that overexpressing Hsp70 with CM-695, a dual inhibitor of HDAC6 and phosphodiesterase 9, protects against thrombosis while leaves bleeding tendency unaltered. METHODS CM-695 was used to induce Hsp70 overexpression. Hsp70 overexpressing mice were submitted to three thrombosis-triggering procedures. The ferric chloride carotid artery model was used to compare the antithrombotic role of CM-695 and rivaroxaban, a direct oral anticoagulant. The mouse tail transection model was used to compare the bleeding tendency upon CM-695 or rivaroxaban administration. RESULTS Intraperitoneal (i.p.) 20 mg/kg CM-695 increased Hsp70 expression markedly in the murine aortic tissue. This treatment delayed thrombosis in the collagen/epinephrine [P=0.04 (Log-Rank test), n=10], Rose Bengal/laser [median vessel occlusion time (OT): 58.6 vs. 39.0 minutes (min) in the control group (CG), P=0.008, n≥10] and ferric chloride (OT: 14.7 vs. 9.2 min in the CG, P=0.032, n≥10) models. I.p. 80 mg/kg CM-695 (n≥9) and intravenous 3 mg/kg rivaroxaban (n≥8) significantly delayed thrombosis. CM-695 did not induce bleeding [median bleeding time (BT): 8.5 vs. 7.5 min in the CG, n≥10]. However, this was dramatically increased by rivaroxaban (BT: 30.0 vs. 13.7 min in the CG, P=0.001, n=10). CONCLUSIONS CM-695 is a new antithrombotic drug devoid of bleeding risk that may be envisioned as a useful clinical tool.

2020-01-13 | GSE93958 | GEO

Genome-wide DNA methylation analysis in permanent atrial fibrillation

Project description:Atrial fibrillation (AF) is the most common sustained arrhythmia with increased risk of stroke and congestive heart failure. AF is a highly genetic heterogeneous disease, but a large proportion of AF cannot be explained by genetic variants only. Some risk factors of AF, tendentious heritable phenomenon, potentially reversible conditions and some subtypes without DNA sequence variation all indicate the participation of DNA methylation in the pathogenesis of AF. Bisulphite converted DNA from the 11 left atrium samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip GPL13534

2014-10-28 | E-GEOD-62727 | biostudies-arrayexpress

Genome-wide DNA methylation analysis in permanent atrial fibrillation

2014-10-28 | GSE62727 | GEO

Comparison of atrial appendage tissues of patients with Valvular Heart Disease and patients with Valvular Heart Disease-Atrial Fibrillation

Project description:Atrial fibrillation (AF) is the most common heart arrhythmia disease. The greatest risk of atrial fibrillation is stroke, and stroke caused by valvular heart disease with atrial fibrillation (AF-VHD) is more serious. the development mechanism from VHD to AF-VHD is not yet clear. The research on expression profiles of lncRNA and mRNA is helpful to explore molecular mechanism in patients with valvular heart disease who develop atrial fibrillation.

2018-04-12 | GSE113013 | GEO

Homo sapiens

Project description:Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis with no increased bleeding risk

| PRJNA277813 | ENA

IKACH IS CONSTITUTIVELY ACTIVE VIA PKC EPSILON IN AGING MEDIATED ATRIAL FIBRILLATION

Project description:Atrial fibrillation (AF), the most common abnormal heart rhythm, is a major cause for stroke. Aging is the greatest risk factor for AF, however, specific ionic pathways that can elucidate how aging leads to AF remain elusive. We used young and old wild type (WT) and PKC epsilon (PKCepsilon) knockout (KO) mice, whole animal, and cellular electrophysiology, as well as whole heart, and cellular imaging to investigate how aging leads to the aberrant functioning of a potassium current, and consequently to AF facilitation. Our experiments showed that knocking out PKC epsilon abrogates the effects of aging on AF by preventing the development of a constitutively active acetylcholine sensitive inward rectifier potassium current (IKACh). Moreover, blocking this abnormal current in the old heart prevents AF inducibility. Our studies demonstrate that in the aging heart, IKACh is constitutively active in a PKC epsilon dependent manner, contributing to the perpetuation of AF

2022-10-07 | MSV000090489 | MassIVE

Decoding the PITX2 controlled genetic network in atrial fibrillation

Project description:Atrial fibrillation (AF), the most common sustained cardiac arrhythmia and a major risk factor for stroke, often arises through ectopic electrical impulses derived from the pulmonary veins (PV). Sequence variants in enhancers controlling expression of the transcription factor PITX2, which is expressed in the cardiomyocytes (CMs) of the PV and left atrium (LA), have been implicated in AF predisposition. Single nuclei multiomic profiling of RNA and analysis of chromatin accessibility combined with spectral clustering uncovered distinct PV- and LA-enriched CM cell states. Pitx2 mutant PV and LA CMs exhibited gene expression changes consistent with cardiac dysfunction through cell-type-distinct, PITX2-directed, cis-regulatory grammars controlling target gene expression. The perturbed network targets in each CM were enriched in distinct human AF-predisposition genes, suggesting combinatorial risk for AF-genesis. Our data further reveals that PV and LA Pitx2 mutant CMs signal to endothelial and endocardial cells through BMP10 signaling with pathogenic potential. This work provides a multiomic framework for interrogating the basis of AF-predisposition in the PV of humans.

2022-04-28 | GSE183310 | GEO

Meta-analysis of Genome-wide Associations and Polygenic Risk Prediction for Atrial Fibrillation in More Than 180,000 Cases

Project description:Atrial fibrillation (AF) is the most common abnormality of heart rhythm and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies (GWAS) increased the power to detect single-nucleotide variant (SNV) associations, and we report more than 350 AF-associated genetic loci. At 139 loci we identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication. We next assayed chromatin accessibility by ATAC-seq and histone H3 Lysine 4 trimethylation in stem cell derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility of our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, we found that a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known AF risk loci will facilitate a greater understanding of the pathways underlying this heart rhythm disorder.

2024-02-08 | GSE225293 | GEO

Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury [20-0174 RNA-seq]

Project description:While thrombin is the key protease in regard to thrombus formation, other coagulation proteases, such as fXa or activated protein C (aPC), independently modulate intracellular signaling via partially disjunct receptors. Hence, we postulate that inhibition of fXa or fIIa conveys different effects in myocardial ischemia-reperfusion injury (IRI) in regard to inflammation despite comparable anticoagulant efficacy.

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