Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:556-562
© 2000 American Heart Association, Inc.
Thrombosis |
HMG CoA Reductase Inhibitors Reduce Plasminogen Activator Inhibitor-1 Expression by Human Vascular Smooth Muscle and Endothelial Cells
From Brigham & Women’s Hospital and Harvard Medical School, Department of Medicine, Vascular Medicine and Atherosclerosis Unit, Boston, Mass.
Correspondence to Peter Libby, MD, Brigham & Women’s Hospital, Vascular Medicine & Atherosclerosis Unit, 221 Longwood Ave, LMRC-309, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
Abstract—The clinical benefit of
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(statins) may derive from a qualitative, functional change in
atherosclerotic lesions in addition to their lipid-lowering properties.
We examined whether statins altered expression of the major
determinants of fibrinolytic balance, plasminogen
activator inhibitor-1 (PAI-1), and tissue-type
plasminogen activator (tPA) in human vascular
smooth muscle (SMC) and endothelial (EC) cells.
Simvastatin reduced levels of PAI-1 antigen released from
SMCs and ECs stimulated with platelet-derived growth factor or
transforming growth factor-ß (IC50 
1 µmol/L).
Levels of EC-derived tPA increased 2-fold over the same concentrations
of simvastatin that inhibited release of PAI-1.
Simvastatin’s inhibitory effect was mimicked
by C3 exoenzyme and prevented by geranylgeranyl pyrophosphate, but not
by farnesyl pyrophosphate, suggesting the involvement of
geranylgeranyl-modified intermediates. Decreased PAI-1 antigen was
correlated with reduced mRNA transcription and activity of the PAI-1
promoter. By inhibiting expression of PAI-1 from SMCs and ECs while
increasing expression of tPA from ECs, simvastatin may
alter the local fibrinolytic balance within the vessel wall toward
increased fibrinolytic capacity that, in turn, would reduce thrombotic
risk after plaque rupture.
Key Words: atherosclerosis • HMG CoA reductase inhibitors • fibrinolysis • plasminogen activator inhibitor-1 • tissue plasminogen activator
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