The Adipocyte and Hemostatic Balance in Obesity: Studies of PAI-1

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 18, No. 1The Adipocyte and Hemostatic Balance in Obesity Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessOtherPDF/EPUBThe Adipocyte and Hemostatic Balance in Obesity Studies of PAI-1 David J. Loskutoff and Fahumiya Samad David J. LoskutoffDavid J. Loskutoff From the Department of Vascular Biology, The Scripps Research Institute, La Jolla, Calif. and Fahumiya SamadFahumiya Samad From the Department of Vascular Biology, The Scripps Research Institute, La Jolla, Calif. Originally published1 Jan 1998https://doi.org/10.1161/01.ATV.18.1.1Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18:1–6Plasminogen 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.Properties of PAI-1PAI-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 (≈3.5×107 [mol/L] −1 · s−1) is at least two orders of magnitude higher than that of other PAIs.1234 The normal concentration of PAI-1 protein in human plasma ranges from 6 to 80 ng/mL with a geometric mean at 24 ng/mL, whereas that of tissue-type PA is 5 to 10 ng/mL. Abnormalities in the concentration of PAI-1 are frequently associated with vascular disease. For example, the inhibitor is elevated in a variety of thrombotic conditions, including myocardial infarction and deep venous thrombosis. Elevated PAI-1 also correlates with thrombosis in animal models, and transgenic mice that overexpress PAI-1 have been reported to develop venous thrombosis.5 On the other hand, the absence of PAI-1 in humans leads to life-long bleeding problems presumably resulting from the development of a hyperfibrinolytic state, and disruption of the PAI-1 gene in mice is also associated with a mild hyperfibrinolytic state as manifested by increased resistance to endotoxin-induced thrombosis.5 Finally, neutralizing plasma PAI-1 activity with specific antibodies or by the use of PAI-1 inhibitors46 enhances spontaneous or tissue-type PA–mediated thrombolysis. These observations emphasize that imbalances in the PA/PAI-1 ratio are likely to promote either thrombosis or bleeding. As summarized in the next section, this balance is severely disturbed in obesity/NIDDM.PAI-1 itself is a single-chain glycoprotein (13% carbohydrate) of ≈Mr 50 000 and consists of 379 amino acids, although some amino-terminal heterogeneity has been reported. It lacks cysteines but contains multiple methionines, which may account for its susceptibility to irreversible inactivation by oxidizing agents. The reactive center of the inhibitor (Arg346/Met347) is contained within the exposed "strained loop" region at the carboxy terminus of the molecule and serves as a pseudosubstrate for the target serine protease. Inhibition of PAs by PAI-1 occurs in a rapid and stoichiometric manner, resulting in the formation of a covalent bond between the two molecules. The inhibitor is consumed in the process, giving rise to the term "suicide inhibitor." PAI-1 is ≈30% homologous with α1-antitrypsin and antithrombin III and is thus a member of the serine protease inhibitor (serpin) superfamily. The general structure of active PAI-1 is similar to that of other serpins, since it appears to be in a stressed conformation that is sensitive to thermal denaturation. The human PAI-1 gene is ≈12.2 kbp long, is organized into 9