The Activation of Plasminogen Activator Inhibitor-1 Expression by IL-1β Is Attenuated by Estrogen in Hepatoblastoma HepG2 Cells Expressing Estrogen Receptor α

Edward J. Kilbourne; Marshall S. Scicchitano

doi:10.1055/s-0037-1614489

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 81(03): 423-427
DOI: 10.1055/s-0037-1614489

Review Article

Schattauer GmbH

The Activation of Plasminogen Activator Inhibitor-1 Expression by IL-1β Is Attenuated by Estrogen in Hepatoblastoma HepG2 Cells Expressing Estrogen Receptor α

Edward J. Kilbourne

¹From the Women’s Health Research Institute, Wyeth-Ayerst Research, Radnor, PA, USA

,

Marshall S. Scicchitano

¹From the Women’s Health Research Institute, Wyeth-Ayerst Research, Radnor, PA, USA

› Author Affiliations

Abstract

Summary

A low estrogen status in postmenopausal women is associated with elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1). In this study, the ability of estrogen compounds to regulate PAI-1 expression was determined in a hepatocyte HepG2 cell line made to stably express estrogen receptor α (ERα). In both the wild type and ER expressing HepG2 cells, estrogen had no effect on basal PAI-1 expression. However, in the ER expressing cells the ability of IL-1β to increase PAI-1 mRNA and protein levels was attenuated by 17β-estradiol, tamoxifen and twelve estrogen components of Premarin. In contrast, the mixed agonist/antagonist raloxifene had weak agonist activity and like the pure antagonist ICI 182780, it dose dependently blocked the effect of 17β-estradiol on IL-1β stimulated PAI-1 levels. These results suggest that estrogen agonists may lower PAI-1 levels in vivo by inhibiting cytokine activated PAI-1 expression by an ER dependent mechanism.

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References

References
1 Juhan-Vague I, Alessi M, Nalbone G. Fibrinolysis and atherothrombosis. Curr Opin Lipidol 1993; 4: 477-83.
2 Carmeliet P, Collen D. Molecular genetics of the fibrinolytic system in haemostasis, thrombogenesis, restenosis and atherosclerosis. Curr Opin Lipidol 1997; 8: 118-25.
3 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; ii: 3-9.
4 Eriksson P, Kallin B, Hooft V, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-5.
5 Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, Humphries SE, Evans A, Luc G, Cambou JP, Arveiler D, Henney AM, Cambien F. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost 1995; 74: 837-41.
6 ECAT Angina Pectoris Study Group. ECAT angina pectoris study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J 1993; 14: 8-17.
7 Juhan-Vague I, Alessi MC. PAI-1, obesity, insulin resistance and risk of cardiovascular events. Thromb Haemost 1997; 78: 656-60.
8 Emeis JJ, Kooistra T. Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J Exp Med 1986; 163: 1260-6.
9 Sawdey M, Loskutoff D. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. J Clin Invest 1991; 88: 1346-53.
10 Levi M, ten Cate H, van der Poll T, van Deventer SJH. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1987; 270: 975-9.
11 Ridker PM. Fibrinolytic and inflammatory markers for arterial occlusion: the evolving epidemiology of thrombosis and hemostasis. Thromb Haemost 1997; 78: 53-9.
12 Gebara O, Mittleman M, Sutherland P, Lipinska I, Matheney T, Xu P, Welty F, Wilson P, Levy D, Muller J, Tofler G. Association between increased estrogen status and increased fibrinolytic potential in the Framingham offspring study. Circulation 1995; 91: 1952-8.
13 Caputo M, Mantini G, Floriani I, Ciceri M, Noseda A, Bonomo L. Tissue plasminogen activator, tissue plasminogen activator inhibitor and lipo-protein (a) in patients with coronary, epiaortic and peripheral occlusive artery disease. Eur Heart J 1996; 17: 1329-36.
14 Schneiderman J, Sawdey MS, Keeton MR, Bordin GM, Bernstein EF, Dilley RB, Loskutoff DJ. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci USA 1992; 89: 6998-7002.
15 Sironi L, Mussoni L, Prati L, Baldassarre D, Camera M, Banfi C, Tremoli E. Plasminogen activator inhibitor type-1 synthesis and mRNA expression in HepG2 cells are regulated by VLDL. Arterioscler Thromb Vasc Biol 1996; 16: 89-96.
16 Koh KK, Mincemoyer R, Bui M, Csako G, Pucino F, Guetta V, Waclawiw M, Cannon R. Effects of hormone replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997; 336: 683-90.
17 Kroon U, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables. Thromb Haemost 1994; 71: 420-23.
18 Meilahn EN, Cauley JA, Tracy RP, Macy EO, Gutai JP, Kuller LH. Association of sex hormones and adiposity with plasma levels of fibrinogen and PAI 1 in postmenopausal women. Am J Epidemiol 1996; 143: 159-66.
19 Gensini GF, Micheli S, Prisco D, Abbate R. Menopause and risk of cardiovascular disease. Thromb Res 1996; 84: 1-19.
20 Scarabin P-Y, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997; 17: 3071-8.
21 Belchetz PE. Hormonal treatment of postmenopausal women. N Engl J Med 1994; 330: 1062-71.
22 Hopkins WE, Fujii S, Sobel BE. Synergistic induction of plasminogen activator inhibitor type-1 in HEP G2 cells by thrombin and transforming growth factor-β. Blood 1992; 79: 75-81.
23 Healy AM, Gelehrter TD. Induction of plasminogen activator inhibitor-1 in HepG2 human hepatoma cells by mediators of the acute phase response. J Biol Chem 1994; 269: 19095-100.
24 Stumpf WE, Sar M. Autoradiographic localization of estrogen, androgen, progestin, and glucocorticosteroid in “target tissue” and “nontarget tissue”. In: Receptors and Mechanism of Action of Steroid Hormones. Part I. Pasqualini JR. (eds) New York: Marcel Dekker; 1976: 41-84.
25 Porter LE, Elm MS, van Thiel DH, Dugas MC, Eagon PK. Characterization and quantification of human hepatic estrogen receptor. Gastroenterology 1983; 84: 704-12.
26 Aten RF, Dickson RB, Eisenfeld AJ. Estrogen receptor in adult male rat liver. Endocrinology 1978; 103: 1629-35.
27 Kooistra T, Bosma PJ, Jespersen J, Kluft C. Studies on the mechanism of action of oral contraceptives with regard to fibrinolytic variables. Am J Obstet Gynecol 1990; 163: 404-12.
28 Graham FL, der Eb AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 1973; 52: 456-67.
29 Harnish DC, Malik S, Karathanasis SK. Activation of apolipoprotein AI gene transcription by the liver-enriched factor HNF-3. J Biol Chem 1994; 269: 28220-6.
30 Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual. 2nd ed.. Ford N, Nolan C, Ferguson M. eds Cold Spring Harbor Laboratory; Cold Spring Harbor, New York: 1989
31 Katzenellenbogen BS, Montano MM, Le Goff P, Schodin DJ, Kraus WL, Bhardwaj B, Fujimoto N. Antiestrogens: mechanisms and actions in target cells. J Steroid Biochem Mol Biol 1995; 53: 387-93.
32 Mitlak BH, Cohen FJ. In search of optimal long-term female hormone replacement: the potential of selective estrogen receptor modulators. Horm Res 1997; 48: 155-63.
33 Walsh BW, Kuller LH, Wild RA, Paul S, Shah A, Anderson PW. The effect of raloxifene on markers of cardiovascular risk in healthy, postmenopausal women. Abstracts of the 11th International Symposium on Atherosclerosis. Atherosclerosis 1997; 134: 182.
34 Kuiper J, Otter M, Voorschuur AH, van Zonneveld AJ, Rijken DC, van Berkel ThJC. Characterization of the interaction of a complex of tissue-type plasminogen activator and plasminogen activator type 1 with rat liver cells. Thromb Haemost 1995; 74: 1298-304.
35 van Kesteren PJM, Kooistra T, Lansink M, van Kamp GJ, Asscheman H, Gooren LJG, Emeis JJ, Vischer UM, Stehouwer CDA. The effects of sex steroids on plasma levels of marker proteins of endothelial cell functioning. Thromb Haemost 1998; 79: 1029-33.
36 Kounnas MZ, Henkin J, Argraves WS, Strickland DK. Low density lipoprotein receptor-related protein/α2-macroglobulin receptor mediates cellular uptake of prourokinase. J Biol Chem 1993; 268: 21862-7.
37 Bu G, Maksymovitch EA, Schwartz AL. Receptor-mediated endocytosis of tissue-type plasminogen activator by low density lipoprotein receptor-related protein on human hepatoma HepG2 cells. J Biol Chem 1993; 268: 13002-9.