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. 1995 Mar 14;92(6):1851–1855. doi: 10.1073/pnas.92.6.1851

Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction.

P Eriksson 1, B Kallin 1, F M van 't Hooft 1, P Båvenholm 1, A Hamsten 1
PMCID: PMC42380  PMID: 7892190

Abstract

Increased plasminogen-activator inhibitor 1 (PAI-1) activity is a common finding in patients with coronary heart disease. Here we provide evidence for an independent, etiological role of PAI-1 in myocardial infarction. The 4G allele of a recently described common 4/5-guanine-tract (4G/5G) polymorphism in the PAI-1 promoter is associated with higher plasma PAI-1 activity. The prevalence of the 4G allele is significantly higher in patients with myocardial infarction before the age of 45 than in population-based controls (allele frequencies of 0.63 vs. 0.53). Both alleles bind a transcriptional activator, whereas the 5G allele also binds a repressor protein to an overlapping binding site. In the absence of bound repressor, the basal level of PAI-1 transcription is increased.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alksnis M., Barkhem T., Strömstedt P. E., Ahola H., Kutoh E., Gustafsson J. A., Poellinger L., Nilsson S. High level expression of functional full length and truncated glucocorticoid receptor in Chinese hamster ovary cells. Demonstration of ligand-induced down-regulation of expressed receptor mRNA and protein. J Biol Chem. 1991 Jun 5;266(16):10078–10085. [PubMed] [Google Scholar]
  2. Carlson K. Lipoprotein fractionation. J Clin Pathol Suppl (Assoc Clin Pathol) 1973;5:32–37. doi: 10.1136/jcp.s1-5.1.32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Carmeliet P., Schoonjans L., Kieckens L., Ream B., Degen J., Bronson R., De Vos R., van den Oord J. J., Collen D., Mulligan R. C. Physiological consequences of loss of plasminogen activator gene function in mice. Nature. 1994 Mar 31;368(6470):419–424. doi: 10.1038/368419a0. [DOI] [PubMed] [Google Scholar]
  4. Carmeliet P., Stassen J. M., Schoonjans L., Ream B., van den Oord J. J., De Mol M., Mulligan R. C., Collen D. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest. 1993 Dec;92(6):2756–2760. doi: 10.1172/JCI116893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cortellaro M., Cofrancesco E., Boschetti C., Mussoni L., Donati M. B., Cardillo M., Catalano M., Gabrielli L., Lombardi B., Specchia G. Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case-control study. The PLAT Group. Arterioscler Thromb. 1993 Oct;13(10):1412–1417. doi: 10.1161/01.atv.13.10.1412. [DOI] [PubMed] [Google Scholar]
  6. Dawson S. J., Wiman B., Hamsten A., Green F., Humphries S., Henney A. M. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem. 1993 May 25;268(15):10739–10745. [PubMed] [Google Scholar]
  7. Erickson L. A., Fici G. J., Lund J. E., Boyle T. P., Polites H. G., Marotti K. R. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature. 1990 Jul 5;346(6279):74–76. doi: 10.1038/346074a0. [DOI] [PubMed] [Google Scholar]
  8. Eriksson P., Wrange O. Protein-protein contacts in the glucocorticoid receptor homodimer influence its DNA binding properties. J Biol Chem. 1990 Feb 25;265(6):3535–3542. [PubMed] [Google Scholar]
  9. Galas D. J., Schmitz A. DNAse footprinting: a simple method for the detection of protein-DNA binding specificity. Nucleic Acids Res. 1978 Sep;5(9):3157–3170. doi: 10.1093/nar/5.9.3157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hamsten A., de Faire U., Walldius G., Dahlén G., Szamosi A., Landou C., Blombäck M., Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987 Jul 4;2(8549):3–9. doi: 10.1016/s0140-6736(87)93050-9. [DOI] [PubMed] [Google Scholar]
  11. Kalb V. F., Jr, Bernlohr R. W. A new spectrophotometric assay for protein in cell extracts. Anal Biochem. 1977 Oct;82(2):362–371. doi: 10.1016/0003-2697(77)90173-7. [DOI] [PubMed] [Google Scholar]
  12. Keeton M. R., Curriden S. A., van Zonneveld A. J., Loskutoff D. J. Identification of regulatory sequences in the type 1 plasminogen activator inhibitor gene responsive to transforming growth factor beta. J Biol Chem. 1991 Dec 5;266(34):23048–23052. [PubMed] [Google Scholar]
  13. Keeton M., Eguchi Y., Sawdey M., Ahn C., Loskutoff D. J. Cellular localization of type 1 plasminogen activator inhibitor messenger RNA and protein in murine renal tissue. Am J Pathol. 1993 Jan;142(1):59–70. [PMC free article] [PubMed] [Google Scholar]
  14. Kruithof E. K., Tran-Thang C., Ransijn A., Bachmann F. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood. 1984 Oct;64(4):907–913. [PubMed] [Google Scholar]
  15. Lew D. J., Decker T., Strehlow I., Darnell J. E. Overlapping elements in the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferons. Mol Cell Biol. 1991 Jan;11(1):182–191. doi: 10.1128/mcb.11.1.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lucore C. L., Fujii S., Wun T. C., Sobel B. E., Billadello J. J. Regulation of the expression of type 1 plasminogen activator inhibitor in Hep G2 cells by epidermal growth factor. J Biol Chem. 1988 Nov 5;263(31):15845–15848. [PubMed] [Google Scholar]
  17. Lupu F., Bergonzelli G. E., Heim D. A., Cousin E., Genton C. Y., Bachmann F., Kruithof E. K. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb. 1993 Jul;13(7):1090–1100. doi: 10.1161/01.atv.13.7.1090. [DOI] [PubMed] [Google Scholar]
  18. Malmberg K., Båvenholm P., Hamsten A. Clinical and biochemical factors associated with prognosis after myocardial infarction at a young age. J Am Coll Cardiol. 1994 Sep;24(3):592–599. doi: 10.1016/0735-1097(94)90002-7. [DOI] [PubMed] [Google Scholar]
  19. Maxam A. M., Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. doi: 10.1073/pnas.74.2.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Meade T. W., Ruddock V., Stirling Y., Chakrabarti R., Miller G. J. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet. 1993 Oct 30;342(8879):1076–1079. doi: 10.1016/0140-6736(93)92062-x. [DOI] [PubMed] [Google Scholar]
  21. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Proudler A. J., Godsland I. F., Stevenson J. C. Insulin propeptides in conditions associated with insulin resistance in humans and their relevance to insulin measurements. Metabolism. 1994 Apr;43(4):446–449. doi: 10.1016/0026-0495(94)90074-4. [DOI] [PubMed] [Google Scholar]
  23. Riccio A., Pedone P. V., Lund L. R., Olesen T., Olsen H. S., Andreasen P. A. Transforming growth factor beta 1-responsive element: closely associated binding sites for USF and CCAAT-binding transcription factor-nuclear factor I in the type 1 plasminogen activator inhibitor gene. Mol Cell Biol. 1992 Apr;12(4):1846–1855. doi: 10.1128/mcb.12.4.1846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schneiderman J., Sawdey M. S., Keeton M. R., Bordin G. M., Bernstein E. F., Dilley R. B., Loskutoff D. J. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6998–7002. doi: 10.1073/pnas.89.15.6998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Simpson A. J., Booth N. A., Moore N. R., Bennett B. Distribution of plasminogen activator inhibitor (PAI-1) in tissues. J Clin Pathol. 1991 Feb;44(2):139–143. doi: 10.1136/jcp.44.2.139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sobey W. J., Beer S. F., Carrington C. A., Clark P. M., Frank B. H., Gray I. P., Luzio S. D., Owens D. R., Schneider A. E., Siddle K. Sensitive and specific two-site immunoradiometric assays for human insulin, proinsulin, 65-66 split and 32-33 split proinsulins. Biochem J. 1989 Jun 1;260(2):535–541. doi: 10.1042/bj2600535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Stiko-Rahm A., Hultgårdh-Nilsson A., Regnström J., Hamsten A., Nilsson J. Native and oxidized LDL enhances production of PDGF AA and the surface expression of PDGF receptors in cultured human smooth muscle cells. Arterioscler Thromb. 1992 Sep;12(9):1099–1109. doi: 10.1161/01.atv.12.9.1099. [DOI] [PubMed] [Google Scholar]
  28. Stiko-Rahm A., Wiman B., Hamsten A., Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis. 1990 Nov-Dec;10(6):1067–1073. doi: 10.1161/01.atv.10.6.1067. [DOI] [PubMed] [Google Scholar]
  29. Tornvall P., Båvenholm P., Landou C., de Faire U., Hamsten A. Relation of plasma levels and composition of apolipoprotein B-containing lipoproteins to angiographically defined coronary artery disease in young patients with myocardial infarction. Circulation. 1993 Nov;88(5 Pt 1):2180–2189. doi: 10.1161/01.cir.88.5.2180. [DOI] [PubMed] [Google Scholar]
  30. Westerhausen D. R., Jr, Hopkins W. E., Billadello J. J. Multiple transforming growth factor-beta-inducible elements regulate expression of the plasminogen activator inhibitor type-1 gene in Hep G2 cells. J Biol Chem. 1991 Jan 15;266(2):1092–1100. [PubMed] [Google Scholar]
  31. Wiman B., Hamsten A. Impaired fibrinolysis and risk of thromboembolism. Prog Cardiovasc Dis. 1991 Nov-Dec;34(3):179–192. doi: 10.1016/0033-0620(91)90012-b. [DOI] [PubMed] [Google Scholar]
  32. Wrange O., Carlstedt-Duke J., Gustafsson J. A. Stoichiometric analysis of the specific interaction of the glucocorticoid receptor with DNA. J Biol Chem. 1986 Sep 5;261(25):11770–11778. [PubMed] [Google Scholar]

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