Identification of Eight Novel Single-Nucleotide Polymorphisms at Human Tissue-type Plasminogen Activator (t-PA) Locus: Association with Vascular t-PA Release In Vivo

Ladenvall, Per; Wall, Ulrika; Jern, Sverker; Jern, Christina

doi:10.1055/s-0037-1613990

Cited by 52 publications

(92 citation statements)

References 29 publications

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“…This process can probably explain spontaneous reperfusion in acute MI. In line with this hypothesis, it has been found that subjects carrying a variant of the t-PA gene with a low capacity for t-PA release are at greater risk of suffering a MI [4,5]. This finding was recently reproduced in the Framingham cohort [6].…”

Section: Introductionmentioning

confidence: 85%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation.Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate procarboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a lowmolecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU.In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5-and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t-PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The profibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU.In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thromboprotective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.

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Section: Introductionmentioning

confidence: 85%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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“…Eight novel polymorphisms were identified, 3 of which were in strong linkage disequilibrium with the Alu polymorphism and consequently, associated with t-PA release: Ϫ7351C/T in the upstream enhancer, 20 099T/C in exon 6, and 27 445T/A in intron 10. 70 The Ϫ7351 promoter polymorphism is located within an Sp1 binding site, whereas the coding region polymorphisms are silent. A population-based, prospective, case-control study found a Ͼ 2.5-fold increase in risk of MI among carriers of the Ϫ7531T allele, 71 which is in accordance with its reduced binding affinity to Sp1.…”

Section: Tissue-type Plasminogen Activatormentioning

confidence: 99%

Genetic Determinants of Arterial Thrombosis

Voetsch

Loscalzo

2004

ATVB

158

112

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Abstract-Arterial thrombosis is a complex disorder that involves multiple genetic and environmental factors interacting to produce the characteristic phenotype. In the past decades, investigators have focused on the molecular genetics of arterial vascular disorders and have identified numerous polymorphisms and mutations in genes related to the hemostatic system and to enzymes involved in the synthesis and bioavailability of nitric oxide (NO); however, the relation between most polymorphisms and the risk of coronary artery disease, ischemic stroke, and peripheral vascular disease remains highly controversial. In this review, we describe the most common genetic variations involved in the pathogenesis of arterial thrombosis, their functional implications, and their association with disease risk. Specifically, we consider polymorphisms in coagulation factors (fibrinogen, prothrombin, FV Leiden, FVII, and FXIII); fibrinolytic factors (tissue-type plasminogen activator, plasminogen activator inhibitor-1, and thrombin-activatable fibrinolysis inhibitor); platelet surface receptors; methylenetetrahydrofolate reductase; endothelial NO synthase; and the antioxidant enzymes paraoxonase and plasma glutathione peroxidase. Overall, there seems to be a modest contribution of individual genetic variants in the hemostatic and antioxidant systems to the risk of arterial thrombosis. Thus, future research ought to focus on identifying novel genetic determinants and on the interaction of these genetic risk factors with each other and the environment to understand better the pathobiology and susceptibility to arterial thrombotic disease.

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“…By resequencing the promoter, the 3Ј untranslated region (3Ј-UTR), and all coding regions of the t-PA gene, 8 novel single-nucleotide polymorphisms (SNPs) were identified. 4 Three of these were associated with t-PA release: Ϫ7351CϾT, 20 099TϾC, and 27 445TϾA. The coding 20 099TϾC SNP is synonymous and the intronic 27 445TϾA SNP is not located in a splice site.…”

Section: Introductionmentioning

confidence: 99%

The t-PA -7351C>T enhancer polymorphism decreases Sp1 and Sp3 protein binding affinity and transcriptional responsiveness to retinoic acid

Wolf

Medcalf

Jern

2004

Blood

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We have previously identified a common polymorphism at the tissue-type plasminogen activator (t-PA) locus (؊7351C>T), located within a GC-box in the retinoic acid (RA) and steroid hormone responsive t-PA enhancer. The aim of the present study was to functionally characterize this t-PA variant. Electrophoretic mobility shift assays (EMSAs) using crude nuclear extracts from human endothelial, HeLa, and NT2 neuronal cells revealed a 10-fold greater protein binding affinity to the wild-

show abstract

Identification of Eight Novel Single-Nucleotide Polymorphisms at Human Tissue-type Plasminogen Activator (t-PA) Locus: Association with Vascular t-PA Release In Vivo

Cited by 52 publications

References 29 publications

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Genetic Determinants of Arterial Thrombosis

The t-PA -7351C>T enhancer polymorphism decreases Sp1 and Sp3 protein binding affinity and transcriptional responsiveness to retinoic acid

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