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J. Biol. Chem., Vol. 276, Issue 19, 15567-15570, May 11, 2001
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From the Edward A. Doisy Department of Biochemistry and Molecular
Biology, Saint Louis University School of Medicine, Saint
Louis, Missouri 63104
Activated protein C (APC) is a natural
anticoagulant in plasma that down-regulates the coagulation cascade by
degrading factors Va and VIIIa. In addition to its anticoagulant
function, APC is also known to possess a profibrinolytic property. This
property of APC has been attributed to its ability to neutralize PAI-1, thereby increasing the concentration of tissue plasminogen activator in
plasma leading to up-regulation of the fibrinolytic cascade. This
hypothesis, however, has not been well established, since the
concentration of PAI-1 in plasma is low, and its reactivity with APC is
very slow in a purified system. Here we demonstrate that vitronectin
enhances the reactivity of PAI-1 with APC ~300-fold making PAI-1 the
most efficient inhibitor of APC thus far reported (k2 = 1.8 × 105
M
ACCELERATED PUBLICATION
Vitronectin Functions as a Cofactor for Rapid Inhibition of
Activated Protein C by Plasminogen Activator Inhibitor-1
IMPLICATIONS FOR THE MECHANISM OF PROFIBRINOLYTIC ACTION OF
ACTIVATED PROTEIN C*
1 s1).
We further show that PAI-1 inhibition of the Glu192 
Gln
mutant of APC is enhanced ~40-fold, independent of vitronectin, suggesting that vitronectin partially overcomes the inhibitory interaction of PAI-1 with Glu192. Additionally, we show
that PAI-1 inhibition of the
Lys37-Lys38-Lys39 Pro-Gln-Glu
mutant of APC is severely impaired, suggesting that, similar to tissue
plasminogen activator, the basic 39-loop of APC plays a critical
role in the reaction. Together, these results suggest that vitronectin
functions as a cofactor to promote the profibrinolytic activity of
APC.
*
This work was supported by Grant R01 HL 62565 (to A. R. R.) awarded by the NHLBI of the National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Biochemistry
and Molecular Biology, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104. Tel.: 314-577-8130; Fax:
314-577-8156; E-mail: rezaiear@slu.edu.
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