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Heterogeneous glycosylation patterns of human PAI-1 may reveal its cellular origin
Authors:Brogren Helén  Sihlbom Carina  Wallmark Karin  Lönn Malin  Deinum Johanna  Karlsson Lena  Jern Sverker
Institution:Clinical Experimental Research Laboratory, Sahlgrenska University Hospital/Ostra, Institute of Medicine, University of Gothenburg, Gothenburg.
Abstract:The main inhibitor of intravascular fibrinolysis is plasminogen activator inhibitor 1 (PAI-1) which binds to and irreversibly inhibits tissue plasminogen activator (tPA). PAI-1 is present in blood, both in platelets and in plasma, and PAI-1 levels are associated with risk of atherothrombosis. Several tissues express PAI-1 but the source of plasma PAI-1 is not known. We recently found that platelets can de novo synthesize PAI-1 and the amount synthesized in vitro in 24 hours is 35-fold higher than required to maintain normal plasma levels. Recombinant human PAI-1 expressed in different cell types or secreted naturally by human cell lines, exhibit heterogeneous glycosylation patterns. The aim of this study was to investigate the hypothesis that platelets might be the source of plasma PAI-1 and that the cellular source of PAI-1 can be determined by its tissue-specific glycosylation pattern. PAI-1 was isolated from platelets, macrophages, endothelial cells, adipose tissue, as well as plasma from lean and obese subjects. The glycosylation was analyzed by nanoLC-MS/MS. PAI-1 isolated from cell lysates and conditioned media from macrophages, endothelial cells, and adipose tissue expressed heterogeneous glycosylation patterns. By contrast, no glycans were detected on PAI-1 isolated from plasma or platelets from healthy lean individuals. Hence, our data suggest that platelets may be the main source of plasma PAI-1 in lean individuals. Interestingly, plasma PAI-1 from obese subjects had a glycan composition similar to that of adipose tissue suggesting that obese subjects with elevated PAI-1 levels may have a major contribution from other tissues.
Keywords:ACD  acid citrate dextrose  BMI  body mass index  CHO  Chinese hamster ovary  HUVEC  human umbilical vein endothelial cell  ICR  ion cyclotron resonance  LTQ-FT  linear ion trap quadrupole-fourier transform  MS  mass spectrometry  MW  molecular weight  PAI-1  plasminogen activator inhibitor 1  PBMC  peripheral blood mononuclear cell  PGE1  prostaglandin e1  PIPES  1  4-piperazinediethanesulfonic acid  ppm  parts per million  TGF-beta  transforming growth factor beta  tPA  tissue type plasminogen activator  
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