Increased risk of venous thromboembolism is associated with genetic variation in heme oxygenase-1 in Blacks

Bean, Christopher J.; Boulet, Sheree L.; Ellingsen, Dorothy; Trau, Heidi A.; Ghaji, Nafisa; Hooper, W. Craig; Austin, Harland

doi:10.1016/j.thromres.2012.08.300

Cited by 9 publications

(9 citation statements)

References 29 publications

(36 reference statements)

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“…Haplotype tagging SNP THSD7A rs2074597 explains part of the chromosomal 7p linkage peak [217]. In addition, an association between venous thromboembolism and genetic variation in HO-1 (HMOX1) [183,218], methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism [219], affected homocysteine levels, and plasminogen activator inhibitor-1(PAI-1) 4G/5G mutation [220]. Furthermore, studies have also associated thromboembolism with other pathophysiological conditions, such as inflammatory bowel disease (IBD) and glioma.…”

Section: Genetic Risk Factors and Venous Thrombosismentioning

confidence: 99%

Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

Wang

Zennadi

2020

IJMS

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Mid-life stage adults are at higher risk of developing venous thrombosis (VT)/thromboembolism (VT/E). Aging is characterized by an overproduction of reactive oxygen species (ROS), which could evoke a series of physiological changes involved in thrombosis. Here, we focus on the critical role of ROS within the red blood cell (RBC) in initiating venous thrombosis during aging. Growing evidence has shifted our interest in the role of unjustifiably unvalued RBCs in blood coagulation. RBCs can be a major source of oxidative stress during aging, since RBC redox homeostasis is generally compromised due to the discrepancy between prooxidants and antioxidants. As a result, ROS accumulate within the RBC due to the constant endogenous hemoglobin (Hb) autoxidation and NADPH oxidase activation, and the uptake of extracellular ROS released by other cells in the circulation. The elevated RBC ROS level affects the RBC membrane structure and function, causing loss of membrane integrity, and decreased deformability. These changes impair RBC function in hemostasis and thrombosis, favoring a hypercoagulable state through enhanced RBC aggregation, RBC binding to endothelial cells affecting nitric oxide availability, RBC-induced platelet activation consequently modulating their activity, RBC interaction with and activation of coagulation factors, increased RBC phosphatidylserine exposure and release of microvesicles, accelerated aging and hemolysis. Thus, RBC oxidative stress during aging typifies an ultimate mechanism in system failure, which can affect major processes involved in the development of venous thrombosis in a variety of ways. The reevaluated concept of the critical role of RBC ROS in the activation of thrombotic events during aging will help identify potential targets for novel strategies to prevent/reduce the risk for VT/E or VT/E recurrences in mid-life stage adults.

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Section: Genetic Risk Factors and Venous Thrombosismentioning

confidence: 99%

Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

Wang

Zennadi

2020

IJMS

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“…The present study speculated that Ccl2, a downstream gene of Klf15, may be the key factor in the effects of Klf15 on DVT formation. A study of the relationship between Hmox1 and DVT was conducted by Bean et al (34) who identified a critical cytoprotective enzyme encoded by the inducible Hmox1 gene with anti-inflammatory, antioxidant and anticoagulant activities in the vascular system. A (GT)n microsatellite located in the promoter of the Hmox1 gene influences the level of the response.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of Klf15‑mediated inhibitory functions in a mouse deep venous thrombosis model

et al. 2020

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Krüppel-like family (KLF) members are important regulators of proinflammatory activation in the vasculature. A transcriptome study involving RNA sequencing (RNA-seq) and quantitative PCR (qPCR) was performed to investigate Klf15 and Klf15-regulated gene levels in C57BL/6 mice with inferior vena cava thrombi and in control (Blank) mice. A total of 2,206 differentially expressed genes (DEGs), including 1,330 upregulated and 876 downregulated genes, were identified between the deep venous thrombosis (DVT) group and the Blank group. Additionally, 1,041 DEGs (235 upregulated and 806 downregulated) were identified between the Klf15-small interfering RNA (siRNA) and Klf15-negative control (NC) groups. The DEGs were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and qPCR was conducted to validate the results. A total of seven significant DEGs were selected from the RNA-seq results. Matrix metalloproteinases (Mmp)12, Mmp13, Mmp19, Arg1, Ccl2, heme oxygenase-1 and Fmo3 levels were significantly higher, while Klf15 levels were lower, in the DVT group than in the Blank group. Fmo3 and Mmp19 have not been previously identified as DVT-associated DEGs. Klf15, Mmp12 and Mmp13 levels were compared between the Klf15-siRNA and Klf15-NC groups. Mmp12 and Mmp13 expression was significantly higher, while that of Klf15 was lower, in the Klf15-siRNA group than in the Klf15-NC group. Critical roles of Klf15, Mmp12 and Mmp13 have been identified, which have not previously been shown to help regulate DVT initiation and progression. Moreover, Klf15-mediated regulation of DVT may be modulated by downregulation of various genes, such as Mmp12 and Mmp13, potentially providing a theoretical foundation and diagnostic criteria for DVT treatment.

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“…However, preclinical and clinical data support the hypothesis that impared hmox-1 activity may increase the initial embolic load and reduce endogenous rate of resolution. [35,36]…”

Section: Discussionmentioning

confidence: 99%

Leukocyte expression of heme oxygenase-1 [hmox1] varies inversely with severity of tricuspid regurgitation in acute pulmonary embolism

Kline

Steuerwald

Watts

et al. 2015

Thrombosis Research

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Objective Pulmonary embolism (PE) can cause intracardiac hemolysis and increased plasma hemoglobin and arginase-1, which can worsen pulmonary vasoconstriction. We test the hypothesis that patients with PE that causes tricuspid regurgitation (TR), indicative of higher pulmonary arterial pressures, have decreased leukocyte expression of hmox-1 compared with patients with PE and no TR and patients without PE. Design Prospective, noninterventional study. Patients Normotensive patients with suspected PE (n=87) who underwent CT pulmonary angiography and transthoracic Doppler-echocardiography. Measurements Significant TR was defined as a jet velocity > 2.7m/s. Leukocyte expression of hmox-1, haptoglobin, haptoglobin related gene, the haptoglobin receptor, CD163 and cox-2 genes were assessed by quantitative rtPCR, and the hmox-1 promoter was examined for the −413 A→T SNP and GT repeat polymorphisms. Results Of the 44 (50%) with PE+, 22 had TR+, and their mean pulmonary vascular occlusion (39±32%) did not differ significantly from patients who were TR− (28±26%, P=0.15). Patients with PE+ and TR+ had significantly lower expression of hmox-1 and haptoglobin genes than patients without PE+ and no TR. Expression of hmox-1 varied inversely with TR velocity (r2=0.45, P<0.001) for PE+ (n=22) but not patients without PE. Hmox-1 expression did not vary significantly with genotype. Cox-2 did not differ between groups and had no correlation with TR. Conclusions Severity of TR varied inversely with hmox-1 expression, suggesting that hmox-1 expression affects pulmonary vascular reactivity after PE.

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Increased risk of venous thromboembolism is associated with genetic variation in heme oxygenase-1 in Blacks

Cited by 9 publications

References 29 publications

Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

Transcriptome analysis of Klf15‑mediated inhibitory functions in a mouse deep venous thrombosis model

Leukocyte expression of heme oxygenase-1 [hmox1] varies inversely with severity of tricuspid regurgitation in acute pulmonary embolism

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