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(Circulation. 1996;93:106-110.)
© 1996 American Heart Association, Inc.
Articles |
Elaboration of Type-1 Plasminogen Activator Inhibitor From Adipocytes
A Potential Pathogenetic Link Between Obesity and Cardiovascular Disease
From the Cardiovascular Division, Washington University School of Medicine (C.H.L., S.L.B., T.K.N.), St Louis, Mo; and the Cardiovascular Division (B.E.S., S.F.), University of Vermont College of Medicine, Burlington, Vt.
Correspondence to Satoshi Fujii, MD, PhD, Cardiovascular Division, University of Vermont, College of Medicine, C-350 Given Bldg, Burlington, VT 05405.
Background Obesity is known to predispose to attenuated fibrinolysis attributable to increased concentrations in plasma of type-1 plasminogen activator inhibitor (PAI-1), the primary physiological inhibitor of endogenous fibrinolysis. PAI-1 is present in neointimal vascular smooth muscle cells and lipid-laden macrophages.
Methods and Results The present study was designed to determine whether PAI-1 expression occurs in adipose tissue as well, thereby potentially contributing to increased cardiovascular risk associated with obesity. 3T3-L1 preadipocytes were differentiated into adipocytes by exposing them to isobutylxanthine (0.5 mmol/L) and dexamethasone (0.25 µmol/L) over 7 days and incubated for 24 hours with transforming growth factor-ß (TGF-ß), known to augment PAI-1 synthesis in several cell types and to be released from platelets when they are activated. TGF-ß increased PAI-1 activity in the conditioned media of the 3T3-L1–derived cells in a concentration-dependent fashion without significantly affecting cell proliferation. Western blotting and immunoprecipitation of 35S-labeled PAI-1 showed that the increased PAI-1 activity paralleled increased PAI-1 protein. Northern blotting showed that increased PAI-1 mRNA preceded increased accumulation of PAI-1 activity and protein in the conditioned media. Furthermore, TGF-ß (10 ng/g body wt) administered in vivo increased PAI-1 activity in mouse plasma and PAI-1 mRNA expression in mouse adipose tissue.
Conclusions Increased plasma PAI-1 activity in obese human
subjects may result from PAI-1 release from an increased mass of
adipose tissue, particularly in association with thrombosis and
elaboration of TGF-ß from platelet 
-granules into the
circulation. The increased PAI-1 may exacerbate vascular disease by
shifting the balance between thrombosis and thrombolysis
toward thrombosis and consequently exposing luminal surfaces of vessels
to mitogens associated with microthrombi over protracted intervals.
Key Words: plasminogen activator inhibitor • adipocyte • obesity • risks
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