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(Circulation. 1995;92:767-772.)
© 1995 American Heart Association, Inc.

Articles

Attenuation of the Synthesis of Plasminogen Activator Inhibitor Type 1 by Niacin

A Potential Link Between Lipid Lowering and Fibrinolysis

Steven L. Brown, MD, PhD; Burton E. Sobel, MD; Satoshi Fujii, MD, PhD

From the Cardiovascular Division, Washington University School of Medicine, St Louis, Mo, and the Cardiovascular Division, the University of Vermont College of Medicine, Burlington.

Correspondence to Satoshi Fujii, MD, PhD, Cardiovascular Division, C-350 Given Bldg, University of Vermont, College of Medicine, Burlington, VT 05405.

Background Plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of endogenous plasminogen activators, has been implicated as a potentiating factor in atherogenesis as well as in coronary thrombosis. We and others have observed attenuation of PAI-1 expression by gemfibrozil both in vivo and in vitro.

Methods and Results To determine whether other lipid-lowering agents with different mechanisms of action exert similar effects, we exposed Hep G2 cells, a highly differentiated human hepatoma cell line, to selected concentrations of niacin. Accumulation of PAI-1 protein, assayed with an ELISA, decreased in conditioned media by 72% in 48 hours in a specific, concentration-dependent fashion. Metabolic labeling experiments demonstrated a decrease in the rate of PAI-1 synthesis. Northern blot analysis demonstrated a preceding, parallel, and specific decrease in the concentration of PAI-1 mRNA. Niacin attenuated the increased PAI-1 synthesis induced by mediators released from thrombi as well. Thus, with 4.25 ng/mL transforming growth factor-ß₁, PAI-1 accumulation increased 4.5-fold in conditioned media in 48 hours. However, niacin attenuated the increase by 65%. Again, both the rate of PAI-1 synthesis and PAI-1 mRNA were reduced. The increased plasma PAI-1 activity and PAI-1 mRNA in liver induced by dexamethasone (0.8 mg IP) in vivo in rats were attenuated by 3 weeks of pretreatment with niacin.

Conclusions These results suggest that niacin, by decreasing PAI-1 expression, may potentiate fibrinolysis, thereby decreasing the stimulation of atherogenesis by clot-associated mitogens associated with microthrombi. Furthermore, the results imply that a pathogenetic link may exist between intracellular lipid metabolism and regulation of expression of fibrinolytic system components.

Key Words: atherosclerosis • fibrinolysis • niacin • plasminogen activators • lipids

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