Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA277813 | ENA |
REPOSITORIES: ENA
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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
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.
2016-04-01 | GSE66724 | GEO
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
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
Project description:Regional differential expression of atrial fibrillation risk genes in the left atrium and pulmonary veins is not well studied, but may yield insights into atrial fibrillation pathogenesis. We tested the hypothesis that there is significant regional differential expression in left atrium structures. RNAseq was performed in 25 regions within the pulmonary veins (n=12), left atrial body (n=10), and left atrial appendage (n=3) from a 75 year old male with hypertension and atrial fibrillation who died of a stroke. These data show that genes involved in atrial fibrillation pathogenesis have substantial regional expression heterogeneity, particularly when comparing the left atrial body, pulmonary veins and left atrial appendage.
2020-11-14 | GSE161450 | GEO
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
Project description:In atrial fibrillation, disturbed electrical conduction disrupts the coordinated contraction of the heart’s antechambers, increasing the risk of stroke and heart failure. The rising prevalence of this disease approaches 9% in patients >65 years. Studying freshly isolated human atrial tissue and a new mouse model, we here decipher how immune and stromal cells contribute to the structural tissue remodeling that underlies atrial fibrillation. Single-cell transcriptomes from control and diseased human atria documented macrophage doubling at the expense of endothelial and mural cells. An inflammatory monocyte and a pro-fibrotic SPP1+ macrophage cluster expanded in patients with atrial fibrillation. To experimentally perturb pathways observed in patients, we matched their risk factors Hypertension, Obesity and Mitral valvE Regurgitation (HOMER) in mice. Atrial single-cell transcriptomes obtained in HOMER mice, which developed enlarged, fibrillation-prone atria, recapitulated human cell composition and transcriptome variations. Recruitment drove the expansion of atrial macrophages; accordingly, inhibition of monocyte migration reduced arrhythmia in Ccr2-/- HOMER mice. Deleting Spp1 established macrophage-derived osteopontin as a pleiotropic signal that promotes atrial fibrillation through pro-fibrotic, inflammatory crosstalk with an arsenal of local immune and stromal cells. Taken together, we identify SPP1+ macrophages as targets for immunomodulatory therapy in atrial fibrillation.
2023-07-13 | GSE224947 | GEO
Project description:In atrial fibrillation, disturbed electrical conduction disrupts the coordinated contraction of the heart’s antechambers, increasing the risk of stroke and heart failure. The rising prevalence of this disease approaches 9% in patients >65 years. Studying freshly isolated human atrial tissue and a new mouse model, we here decipher how immune and stromal cells contribute to the structural tissue remodeling that underlies atrial fibrillation. Single-cell transcriptomes from control and diseased human atria documented macrophage doubling at the expense of endothelial and mural cells. An inflammatory monocyte and a pro-fibrotic SPP1+ macrophage cluster expanded in patients with atrial fibrillation. To experimentally perturb pathways observed in patients, we matched their risk factors Hypertension, Obesity and Mitral valvE Regurgitation (HOMER) in mice. Atrial single-cell transcriptomes obtained in HOMER mice, which developed enlarged, fibrillation-prone atria, recapitulated human cell composition and transcriptome variations. Recruitment drove the expansion of atrial macrophages; accordingly, inhibition of monocyte migration reduced arrhythmia in Ccr2-/- HOMER mice. Deleting Spp1 established macrophage-derived osteopontin as a pleiotropic signal that promotes atrial fibrillation through pro-fibrotic, inflammatory crosstalk with an arsenal of local immune and stromal cells. Taken together, we identify SPP1+ macrophages as targets for immunomodulatory therapy in atrial fibrillation.
2023-07-13 | GSE197518 | GEO
Project description:In atrial fibrillation, disturbed electrical conduction disrupts the coordinated contraction of the heart’s antechambers, increasing the risk of stroke and heart failure. The rising prevalence of this disease approaches 9% in patients >65 years. Studying freshly isolated human atrial tissue and a new mouse model, we here decipher how immune and stromal cells contribute to the structural tissue remodeling that underlies atrial fibrillation. Single-cell transcriptomes from control and diseased human atria documented macrophage doubling at the expense of endothelial and mural cells. An inflammatory monocyte and a pro-fibrotic SPP1+ macrophage cluster expanded in patients with atrial fibrillation. To experimentally perturb pathways observed in patients, we matched their risk factors Hypertension, Obesity and Mitral valvE Regurgitation (HOMER) in mice. Atrial single-cell transcriptomes obtained in HOMER mice, which developed enlarged, fibrillation-prone atria, recapitulated human cell composition and transcriptome variations. Recruitment drove the expansion of atrial macrophages; accordingly, inhibition of monocyte migration reduced arrhythmia in Ccr2-/- HOMER mice. Deleting Spp1 established macrophage-derived osteopontin as a pleiotropic signal that promotes atrial fibrillation through pro-fibrotic, inflammatory crosstalk with an arsenal of local immune and stromal cells. Taken together, we identify SPP1+ macrophages as targets for immunomodulatory therapy in atrial fibrillation.
2023-07-13 | GSE225671 | GEO
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.
2014-10-28 | GSE62727 | GEO