Marburg I Polymorphism of Factor VII–Activating Protease

Willeit, Johann; Kiechl, Stefan; Weimer, Thomas; Mair, A.; Santer, Peter; Wiedermann, Christian J.; Roemisch, Juergen

doi:10.1161/01.cir.0000055189.18831.b1

Cited by 95 publications

(33 citation statements)

References 15 publications

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“…It was recently shown that FSAP reduces cell proliferation of human umbilical vein endothelial cells (52) as well as VSMC (26). Together with the observed presence of FSAP in atherosclerotic lesions and the identification of a single nucleotide polymorphism (Marburg I) as a risk predictor of carotid stenosis (53), FSAP was suggested to be an important inhibitor of the proatherogenic phenotype of VSMC (26). In the present study, we demonstrated that PAI-1 can antagonize the FSAP-mediated inhibition of VSMC proliferation, underscoring the functional relevance of FSAP inhibition by PAI-1 and its possible involvement in cellular activities associated with cell proliferation.…”

mentioning

confidence: 77%

Plasminogen Activator Inhibitor-1 Is an Inhibitor of Factor VII-activating Protease in Patients with Acute Respiratory Distress Syndrome

Wygrecka

Morty

Markart

et al. 2007

Journal of Biological Chemistry

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Factor VII-activating protease (FSAP) is a novel plasma-derived serine protease structurally homologous to tissue-type and urokinase-type plasminogen activators. We demonstrate that plasminogen activator inhibitor-1 (PAI-1), the predominant inhibitor of tissue-type and urokinase-type plasminogen activators in plasma and tissues, is an inhibitor of FSAP as well. We detected PAI-1⅐FSAP complexes in addition to high levels of extracellular RNA, an important FSAP cofactor, in bronchoalveolar lavage fluids from patients with acute respiratory distress syndrome. Hydrolytic activity of FSAP was inhibited by PAI-1 with a second-order inhibition rate constant (K a ) of 3.38 ؎ Factor VII-activating protease (FSAP), 2 also known as plasma hyaluronan-binding protein or plasma hyaluronanbinding serine protease, is a recently described plasma serine protease (1-3), expressed primarily in the liver and found in endothelial and epithelial cells of the lung, kidney, placenta, and pancreas (1, 4). The enzyme circulates as a 64-kDa single-chain zymogen (scFSAP) in plasma, which is autoactivated to an enzymatically active two-chain form (tcFSAP). Two-chain FSAP consists of a 46-kDa heavy chain connected by a disulfide bridge to a 29-kDa light chain containing the catalytic domain (5-7). Autoactivation of scFSAP to tcFSAP is promoted in the presence of negatively charged substances, such as heparin, dextran sulfate, phosphatidylethanolamine, or extracellular RNA (5-8).The role of FSAP in different physiological and pathophysiological conditions is not fully understood. A dual role for FSAP in vitro in hemostasis has been suggested (3, 9). FSAP is a potent activator of coagulation factor VII, thus contributing to the initiation of blood coagulation via the extrinsic pathway (3). Furthermore, FSAP also activates prourokinase-type plasminogen activator (uPA) and thus contributes to plasminogen activation as well (9). Additional links between FSAP and the plasminogen activation system exist; FSAP is highly homologous to uPA and tissue-type plasminogen activator (tPA), and uPA is a potential physiological activator of FSAP (5). Additionally, recent in vitro studies have revealed that hemostatic serine protease inhibitors (serpins), such as C1 inhibitor and ␣ 2 -antiplasmin, are inhibitors of FSAP proteolytic activity (7, 9). These observations prompted us to explore the role of PAI-1, the primary member of this inhibitor family in plasma and tissues (10, 11), as a potential regulator of FSAP. It is known that PAI-1 inhibits uPA and tPA by forming SDS-resistant, catalytically inactive complexes with proteases (12, 13). In this reaction, the reactive center residues P 1 -P 1 Ј (Arg 346 -Met 347 ) in PAI-1 function as an exposed "bait" for the protease by mimicking a putative cleavage site (14 -17). In addition to inhibiting serine proteases, PAI-1 also interacts with different components of the extracellular matrix, including heparin (18, 19) and vitronectin (20 -22). In the presence of heparin, the selectivity of PAI-1 for the inhibition ...

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mentioning

confidence: 77%

Plasminogen Activator Inhibitor-1 Is an Inhibitor of Factor VII-activating Protease in Patients with Acute Respiratory Distress Syndrome

Wygrecka

Morty

Markart

et al. 2007

Journal of Biological Chemistry

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“…9 Rare genetic variants (e.g. the Marburg I polymorphism) in HABP2 have also been associated with increased risk of deep venous thrombosis, 24 carotid stenosis, 25 and stroke. 26 Recent animal studies have also suggested that FSAP activity may modulate stroke-associated brain injury.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2

Cheng¹,

Stanne²,

Giese³

et al. 2016

Stroke

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Background and Purpose Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a two-stage meta-analysis of genome-wide association studies (GWAS), focusing on stroke cases with an age of onset < 60 years old. Methods The Discovery stage of our GWAS included 4,505 cases and 21,968 controls of European, South-Asian and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10−6 and performed in silico association analyses in an independent sample of up to 1,003 cases and 7,745 controls. Results One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the Discovery and Follow-up Stages (rs11196288, OR=1.41, P=9.5×10−9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that two SNPs in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. Conclusions HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

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“…HABP2 is believed to affect vascular smooth muscle cell proliferation and atherosclerotic plaque instability (27). A HABP2 polymorphism has been associated with inhibited activation of prourokinase and progression of carotid stenosis (28), and HABP2 variants have been associated with venous thromboembolic disease (29). …”

Section: Discussionmentioning

confidence: 99%

Carotid Plaque and Candidate Genes Related to Inflammation and Endothelial Function in Hispanics From Northern Manhattan

Gardener

Beecham

Cabral

et al. 2011

Stroke

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BACKGROUND AND PURPOSE The genetic influence on carotid atherosclerotic plaque is mostly unknown. This study examines the association between carotid plaque and single nucleotide polymorphisms (SNPs) in selected genes implicated in inflammation and endothelial function. METHODS A total of 43 genes (197 SNPs) involved in inflammation and endothelial function were interrogated in 287 Dominicans from the Northern Manhattan Study (mean age 64±7 years, 58% women) who had undergone high-resolution B-mode ultrasound for examination of carotid plaque. Using an additive genetic model, multiple logistic regression analyses were conducted, a within gene haplotype analysis was performed and interactions between genes were examined. Results were validated in an independent set of 301 Dominicans. RESULTS Carotid plaque was present in 143(47%) participants. Nine genes had at least one SNP associated (p≤0.01) with carotid plaque phenotypes: TNF, NOS2A, IL6R, TNFSF4, PPARA, IL1A, TLR4, ITGA2, HABP2. SNPs in TNFSF4, PPARA, TLR4, ITGA2, and HABP2 were also implicated with the same carotid phenotype in the validation analysis. Haplotype analysis revealed an additional gene of interest, VCAM1. CONCLUSIONS We report novel associations between variations in ten genes involved in inflammation and endothelial function and carotid plaque phenotypes in a Dominican sample, with replication for five genes in an independent Dominican sample.

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Marburg I Polymorphism of Factor VII–Activating Protease

Cited by 95 publications

References 15 publications

Plasminogen Activator Inhibitor-1 Is an Inhibitor of Factor VII-activating Protease in Patients with Acute Respiratory Distress Syndrome

Plasminogen Activator Inhibitor-1 Is an Inhibitor of Factor VII-activating Protease in Patients with Acute Respiratory Distress Syndrome

Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2

Carotid Plaque and Candidate Genes Related to Inflammation and Endothelial Function in Hispanics From Northern Manhattan

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