Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme biosynthesized in the liver and released into the blood circulation. Activated TAFI (TAFIa) has been implicated as an important player in maintaining the balance between blood coagulation and fibrinolysis. In the present study, regulation of TAFI (CPB2) gene expression was investigated using cultured human hepatoma HepG2 cells. HepG2 cells were treated with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the levels of TAFI antigen and CPB2 mRNA were measured. HepG2 cells treated with LY29400 decreased their release of TAFI antigen into the conditioned medium (CM). In parallel, there were decreased levels of CPB2 mRNA and TAFI antigen in the cells. However, CPB2 gene promoter activity was not influenced by treatment of the cells with LY294002. The half-life of the CPB2 transcript was shortened by treatment with LY294002 compared with control. The present results suggest that the PI3K inhibitor LY294002 suppresses expression of TAFI, a prothrombotic factor, by decreasing the stability of CPB2 transcripts.Key words thrombin-activatable fibrinolysis inhibitor (TAFI); carboxypeptidase; LY294002; Akt; HepG2 cell Thrombin-activatable fibrinolysis inhibitor (TAFI) is a zymogen of carboxypeptidase B (CPB)-like proenzyme that is synthesized in the liver and released into circulating plasma. 1)The active form of TAFI (TAFIa) is generated by cleavage at Arg92 of the proenzyme by the proteolytic activity of thrombin, plasmin, and trypsin. TAFIa exhibits CPB-like activity that specifically cleaves basic amino acids such as arginine and lysine residues located in the carboxyl (C)-termini of peptides. One of the TAFIa substrates is a partially degraded fibrin that contains a C-terminal lysine that provides a high affinity binding sites for tissue type plasminogen activator (tPA) and plasminogen in tPA-dependent plasminogen activation. Thus, TAFIa inhibits fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin, thereby inhibiting development of the positive feedback mechanism in the fibrinolytic cascade.2,3) Indeed, TAFIa attenuates spontaneous fibrinolysis of batroxobin-induced fibrin deposition in rat lungs. 4) TAFIa inhibitors enhance endogenous fibrinolysis, resulting in antithrombotic effects.5,6) Additionally, TAFIa has been shown to remove the C-terminal arginine residues from bradykinin as well as the anaphylatoxins C3a and C5a, thus indicating a role for the TAFI pathway in the vascular response to inflammation and the regulation of fibrinolysis. 7,8)Recent reports showed that a high level of TAFI expression in circulating plasma was a risk factor for thrombotic disorders. Thus, it was shown that elevated TAFI antigen in circulating plasma was a risk factor for premature peripheral arterial disease 9) and recurrent venous thromboembolism. 10) Moreover, TAFI antigen and functional protein levels in human plasma are significantly higher in the acute phase of ischemic stroke.11,12) Importantly,...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.