Transcriptome profiling reveals the endogenous sponging role of LINC00659 and UST-AS1 in high altitude induced thrombosis

2021 ◽  
Author(s):  
Prabhash Kumar Jha ◽  
Aatira Vijay ◽  
Amit Prabhakar ◽  
Tathagata Chatterjee ◽  
Velu Nair ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
High Altitude ◽  
Expression Profile ◽  
Thrombus Formation ◽  
Pearson Correlation ◽  
Coagulation Cascade ◽  
Protein Coding ◽  
Vein Thrombosis ◽  
Protein Coding Genes ◽  
Deep Vein

Background: The pathophysiology of Deep vein thrombosis (DVT) is considered as multifactorial, where thrombus formation is interplay of genetic and acquired risk factors. A little is known about the expression profile and roles of lncRNAs in human subjects developing DVT at high altitude. Methods: Using RNAseq, we compared peripheral blood mRNA and lncRNA expression profile in human High Altitude deep Vein Thrombosis (HA-DVT) patients with high altitude control subjects. We used DESeq to identify differentially expressed (DE) genes. We annotated the long noncoding RNAs using NONCODE 3.0 database. In silico putative lncRNA-miRNA association study unravels the endogenous miRNA sponge associated with our candidate lncRNAs. These findings were validated by siRNA knockdown assay of the candidate lncRNAs conducted in primary endothelial cells. Results: We identified 1524 DE mRNA and 973 DE lncRNAs. Co-expressed protein-coding genes analysis resulted in a list of 722 coexpressed protein-coding genes with a Pearson correlation coefficients >0.7. The functional annotation of co-expressed genes and putative proteins revealed their involvement in the hypoxia, immune response and coagulation cascade. Through its miRNA response elements (MREs) to compete for miR-143 and miR-15, lncRNA-LINC00659 and UXT-AS1 regulates the expression of prothrombotic genes. Furthermore, in vitro RNA interference (siRNA) simultaneously suppressed lncRNAs and target gene mRNA level. Conclusions: This transcriptome profile describes novel potential mechanisms of interaction between lncRNAs, the coding genes, miRNAs and regulatory transcription factors that define the thrombotic signature and may be used in establishing lncRNAs as biomarker in HA-DVT.

Abstract 14771: Iron Plays a Role in the Thrombus Formation of a Rat Model of Deep Vein Thrombosis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Makiko Oboshi ◽  
Yoshiro Naito ◽  
Hisashi Sawada ◽  
Toshihiro Iwasaku ◽  
Yoshitaka Okuhara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Deep Vein Thrombosis ◽  
Cardiovascular Diseases ◽  
Rat Model ◽  
Thrombus Formation ◽  
Dietary Iron ◽  
Iron Restriction ◽  
Vein Thrombosis ◽  
Type Plasminogen Activator ◽  
Deep Vein

Introduction: Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism. On the other hand, iron is an essential element for maintaining physiological homeostasis in the body, whereas excess iron leads to toxicity and free radical damage. Hence, iron accumulation is associated with the pathogenesis of several cardiovascular diseases. We have previously reported that dietary iron restriction (IR) prevents the development of hypertension and chronic kidney disease (CKD) in animal models of several cardiovascular diseases. In addition, we have shown that intracellular iron transport protein, transferrin receptor 1 (TfR1), is involved in the mechanism of several cardiovascular diseases. In this study, we hypothesized that iron and TfR1 play roles in the pathogenesis of DVT. We investigate the effects of dietary IR on the thrombus formation and resolution in a rat model of DVT. Methods: We performed the ligation of inferior vena cava to induce DVT in 8-week-old male Sprague-Dawley rats. After the ligation, rats were given either a normal diet (DVT group) or iron-restricted diet (DVT+IR group). The thrombus was harvested at 5days after the ligation. Results: At first, TfR1 expression was increased in the thrombus of a rat model of DVT, suggesting that iron and TfR1 play roles in the pathogenesis of DVT. Interestingly, dietary iron restriction reduced the thrombus size compared with the DVT group (180±17 mg/cm vs 135±13 mg/cm, DVT vs DVT+IR ; p < 0.05). Intrathrombotic collagen content was diminished in the DVT+IR group compared with the DVT group. Intrathrombotic gene expression and activity of matrix metalloproteinase (MMP)-9 were increased in the DVT+IR group compared with the DVT group. In addition, the numbers of CD68 positive cells in the thrombus were fewer in the DVT+IR group than in the DVT group. Furthermore, intrathrombotic gene expression of urokinase-type plasminogen activator and tissue-type plasminogen activator was higher in the DVT+IR group than in the DVT group. Conclusions: These results suggest that iron plays a role in the pathogenesis of DVT.

Abstract 54: Peptidylarginine Deiminase 4-dependent Generation of Neutrophil Extracellular Traps is Crucial for Deep Vein Thrombosis in Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Kimberly Martinod ◽  
Melanie Demers ◽  
Tobias A Fuchs ◽  
Siu Ling Wong ◽  
Alexander Brill ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Peptidylarginine Deiminase ◽  
Wild Type ◽  
Chromatin Decondensation ◽  
Peptidylarginine Deiminase 4 ◽  
Vein Thrombosis ◽  
Deep Vein ◽  
Deficient Mice

Introduction Histone hypercitrullination by the enzyme peptidylarginine deiminase 4 (PAD4) leads to nuclear chromatin decondensation that is needed for neutrophil extracellular trap (NET) formation. NETs consist of chromatin and granule proteins that are released into the extracellular environment. NETs were shown to be involved in thrombosis by promoting coagulation and platelet adhesion and were identified in the thrombus scaffold in animal models of deep vein thrombosis (DVT). Objective Whether NETs are involved in the pathogenesis of DVT or whether they are merely a consequence of neutrophil recruitment to the thrombus is unknown. We hypothesized that NET formation would be impaired in PAD4-deficient mice during deep vein thrombosis and that this may affect thrombus formation and/or stability. Methods PAD4-deficient mice are incapable of citrullinating histones and therefore fail to decondense chromatin during NETosis. We performed the inferior vena cava stenosis model of DVT in wild-type or PAD4-/- mice. Intravital microscopy was done to assess leukocyte vessel wall interaction in PAD4 deficiency. Results We induced NET formation in isolated peripheral blood mouse neutrophils with ionomycin and found that PAD4-/- neutrophils had a complete inability to produce NETs (WT, 20.65±2.61% NETs; PAD4-/-, not detected. n=4). Leukocyte-endothelial interactions in PAD4-/- mice were not impaired upon induction of systemic Weibel-Palade body release (WT, 55.2±11.8; PAD4-/-, 62.0±17.5 cells/min, n=5-6). In the DVT model, while a majority (9/10) of wild-type mice formed a thrombus 48 hours after stenosis, only 1 of 11 PAD4-/- mice formed a thrombus. Thrombus formation could be rescued by infusions of isolated WT bone marrow neutrophils into PAD4-/- mice, and extracellular H3Cit+ areas were seen within these thrombi. This data suggests that neutrophil PAD4 was essential for thrombus formation in deep veins. Conclusion NETs comprise a crucial part of the pathologic thrombus scaffold, and here we report that the lack of NETs inhibits pathological thrombosis. Chromatin decondensation initiated by PAD4 in neutrophils is a key player in the formation of deep vein thrombi and targeting neutrophil histone modification could be a new way to prevent DVT.

Prevention effect of orally active heparin derivative on deep vein thrombosis

2006 ◽  
Vol 96 (08) ◽  
pp. 149-153 ◽  
Author(s):  
Sang Kim ◽  
Dong Lee ◽  
Choong Kim ◽  
Hyun Moon ◽  
Youngro Byun
Keyword(s):  
Pulmonary Embolism ◽  
Deep Vein Thrombosis ◽  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Sprague Dawley ◽  
Vein Thrombosis ◽  
Sprague Dawley Rats ◽  
Acid Conjugate ◽  
Deep Vein ◽  
Orally Active

SummaryThe use of heparin as the most potent anticoagulant for the prevention of deep vein thrombosis and pulmonary embolism is nevertheless limited, because it is available to patients only by parenteral administration. Toward overcoming this limitation in the use of heparin, we have previously developed an orally active heparin-deoxycholic acid conjugate (LMWH-DOCA) in 10% DMSO formulation. The present study evaluates the anti-thrombogenic effect of this orally active LMWH-DOCA using a venous thrombosis animal model with Sprague-Dawley rats. When 5 mg/kg of LMWH-DOCA was orally administered in rats, the maximum anti-FXa activity in plasma was 0. 35 ± 0. 02, and anti-FXa activity in plasma was maintained above 0. 1 IU/ml [the minimum effective anti-FXa activity for the prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE)] for five hours. LMWH-DOCA (5 mg/kg, 430 IU/kg) that was orally administered reduced the thrombus formation by 56. 3 ± 19. 8%;on the other hand, subcutaneously administered enoxaparin (100 IU/kg) reduced the thrombus formation by 36. 4 ± 14. 5%. Also, LMWH-DOCA was effectively neutralized by protamine that was used as an antidote. Therefore, orally active LMWH-DOCA could be proposed as a new drug that is effective for the longterm prevention of DVT and PE.

C0484: Polymorphisms of the Coagulation Cascade Genes and Age of First Deep Vein Thrombosis Event

2014 ◽  
Vol 133 ◽  
pp. S67
Author(s):  
L. Cocera Ortega ◽  
V. Adam ◽  
M. Jose Fabia ◽  
P. Rentero ◽  
M. Jose Garcia-Fuster ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Coagulation Cascade ◽  
Vein Thrombosis ◽  
Deep Vein

scholarly journals High Altitude Is an Independent Risk Factor for Developing a Pulmonary Embolism, but Not a Deep Vein Thrombosis Following a 1- to 2-Level Lumbar Fusion

2019 ◽  
Vol 9 (7) ◽  
pp. 729-734 ◽  
Author(s):  
Chester J. Donnally ◽  
Ajit M. Vakharia ◽  
Jonathan I. Sheu ◽  
Rushabh M. Vakharia ◽  
Dhanur Damodar ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Risk Factor ◽  
Deep Vein Thrombosis ◽  
High Altitude ◽  
Independent Risk Factor ◽  
Lumbar Fusion ◽  
Vascular Complications ◽  
Prior History ◽  
Vein Thrombosis ◽  
Deep Vein

Study Design: Retrospective study. Objective: To identify if a 1- to 2-level posterior lumbar fusion at higher altitude is an independent risk factor for postoperative deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods: A national Medicare database was queried for all patients undergoing 1- to 2-level lumbar fusions from 2005 to 2014. Those with a prior history of DVT, PE, coagulopathy, or peripheral vascular complications were excluded to better isolate altitude as the dependent variable. The groups were matched 1:1 based on age, gender, and comorbidities to limit potential cofounders. Using ZIP codes of the hospitals where the procedure occurred, we separated our patients into high (>4000 feet) and low (<100 feet) altitudes to investigate postoperative rates of DVTs and PEs at 90 days. Results: Compared with lumbar fusions performed at low-altitude centers, patients undergoing the same procedure at high altitude had significantly higher PE rates ( P = .010) at 90 days postoperatively, and similar rates of 90-day postoperative DVTs ( P = .078). There were no significant differences in age or comorbidities between these cohorts due to our strict matching process ( P = 1.00). Conclusion: Spinal fusions performed at altitudes >4000 feet incurred higher PE rates in the first 90 days compared with patients receiving the same surgery at <100 feet but did not incur higher rates of postoperative DVTs.

Regulation of Tissue Factor by NF-kB Transcription Factor p50 Is Essential for the Pathogeneses of Deep Vein Thrombosis and Arterial Restenosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1458-1458
Author(s):  
Jian-Guo Geng ◽  
Jian-Guo Wang ◽  
Nigel Mackman ◽  
Arne Slungaard ◽  
Yuqing Huo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Deep Vein Thrombosis ◽  
Venous Thrombosis ◽  
Tissue Factor ◽  
Coagulation Cascade ◽  
Vein Thrombosis ◽  
Arterial Restenosis ◽  
Deep Vein

Abstract NF-kB transcription factors regulate the expression of tissue factor (TF), a principal initiator for the coagulation cascade. Dominant among the five cellular members of NF-kB transcription factors is the p50/p65 heterodimer. Here we report that Andrographolide (Andro; a 350-dalton antagonist that targets reduced cysteine62 of p50 for inhibition of NF-kB activation) and genetic deletion of p50 potently attenuated TF activity in stimulated endothelial cells and monocytes/macrophages. The direct binding of p50/p65 heterodimer to the TF-kB site in human TF promoter was demonstrated by p50 and p65 antibody ‘supershift’ using electrophoretic mobility shift assay and immunoprecipitation of the promoter of the human TF gene from chromatins of TNF-a-stimulated human umbilical vein endothelial cells. Andro-treated and p50 null mice both exhibited suppressed TF expression, blunted fibrin deposition, reduced venous thrombosis, and decreased neointimal hyperplasia. Blockade of TF activity by an anti-murine TF antibody also attenuated venous thrombosis and neointimal proliferation in vivo. Our findings thus indicate that NF-kB transcription factor p50 critically regulates TF activity in the pathogeneses of deep vein thrombosis and arterial restenosis, and suggest that specific inhibitors of p50, such as Andro, have the potential to be therapeutically valuable for preventing and perhaps treating arterial and venous thrombosis.

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