© 1998 American Heart Association, Inc.
Brief Review |
The Adipocyte and Hemostatic Balance in Obesity
Studies of PAI-1
From the Department of Vascular Biology, The Scripps Research Institute, La Jolla, Calif.
Correspondence to David J. Loskutoff, PhD, The Scripps Research Institute, Department of Vascular Biology, 10550 N Torrey Pines Rd, VB-3, La Jolla, CA 92037. E-mail loskutof@scripps.edu
Key Words: adipocyte • adipose tissue • insulin • TNF-
• TGF-ß
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Introduction |
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Plasminogen activator inhibitor 1 is the primary physiological inhibitor of plasminogen activation in vivo, and elevations in plasma PAI-1 appear to compromise normal fibrin clearance mechanisms and promote thrombosis. PAI-1 is dramatically upregulated in obesity, a complex condition associated with increased risk for myocardial infarction, accelerated atherosclerosis, hypertension, glucose intolerance, insulin resistance, hyperinsulinemia, and NIDDM. In spite of the apparent link between elevated PAI-1 levels and thrombotic disease, little is known about the origin of this plasma inhibitor in obesity/NIDDM or about the signals that control its biosynthesis. Potential insights into the underlying molecular events have come from recent studies of genetically obese mice and of cultured adipocytes. These studies are reviewed here.* They emphasize the key role played by the adipocyte, a cell whose numbers, size, and metabolic activity are grossly altered in obesity/NIDDM. They also suggest that multiple cytokines, hormones, and growth factors may be involved, and they raise the possibility that the abnormal expression of other hemostatic genes by adipocytes in obesity/NIDDM may also contribute to the cardiovascular complications of this disorder. In this regard, our preliminary studies indicate that TF gene expression is elevated in the adipose tissues of the obese mouse.
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Properties of PAI-1 |
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PAI-1 appears to be the primary physiological inhibitor of plasminogen activation in blood, since it is the only PAI found complexed with single-chain tissue-type PA in carefully collected human plasma, and the second-order rate constant for its interaction with tissue-type PA and urokinase-type PA (
3.5x107 [mol/L]
-1 · s-1) is at
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