Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 2003;34:2828-2829
Published online before print November 20, 2003, doi: 10.1161/01.STR.0000103831.56586.4F
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
34/12/2828    most recent
01.STR.0000103831.56586.4Fv1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Roest, M.
Right arrow Articles by Banga, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Roest, M.
Right arrow Articles by Banga, J. D.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Stroke

(Stroke. 2003;34:2828.)
© 2003 American Heart Association, Inc.

Original Contributions

Editorial Comment— Genetic Make-Up for Increased PAI-1 Expression Protects Against Stroke

Mark Roest, PhD, Guest Editor Jan Dirk Banga, MD, PhD, Guest Editor

Research Laboratory of the Department of Clinical Chemistry, Utrecht University Medical School, Utrecht, the Netherlands
Department of Internal Medicine, Utrecht University Medical School, Utrecht, the Netherlands

This issue of Stroke reports findings that the 4G variant of the PAI-1 4G/5G polymorphism is associated with a reduced incidence of stroke.1 Those findings are in agreement with 7 other studies that observed a similar relationship between the 4G variant of PAI-1 and a reduced stroke risk.2–8 This consistency in 8 independent studies minimizes the possibility that the relationship between the PAI-1 4G variant of PAI-1 and reduced stroke risk is a chance finding.

PAI-1 4G/5G is an interesting "functional" polymorphism because the alleles are the real cause of variation in PAI-1 expression.9 The 4G allele of the PAI-1 4G/5G polymorphism lacks a binding site for a transcription repressor protein, which is present on the 5G allele. Therefore, the 4G is the high PAI-1 expresser allele and the 5G the low expresser allele. Subjects who are homozygous for the 4G allele have 25% higher plasma concentrations than subjects homozygous for the 5G allele.9 Those findings indicate that homozygosity for the 4G allele stands for lifelong exposure to increased PAI-1 expression. The PAI-1 4G/5G polymorphism is an important tool in investigating the etiological involvement of PAI-1 in stroke because genetic make-up is fixed at conception; therefore, an association between genetic make-up for increased PAI-1 expression (PAI-1 4G allele) and a reduced risk of stroke is not confounded by other risk factors of stroke.10 For the same reason, genetic make-up for high PAI-1 expression is not a consequence of stroke. A relationship between the PAI-1 4G allele and a reduced risk of stroke is therefore causal evidence for a protective role of PAI-1 against stroke.

The notion that PAI-1 protects against stroke is further supported by findings in large cohort studies that tPA levels predict an increased incidence of stroke,11,12 while plasma PAI-1 concentrations seem not associated with stroke risk.13 Still, careful consideration is required to draw definite conclusions from observational studies on the relationship between tPA or PAI-1 levels and stroke incidence because plasma variations of tPA and PAI-1 depend on estrogen levels, the renin-angiotensin system, VLDL levels, unsaturated fatty acids content, insuline-like molecules, and pro-inflammatory cytokines (reviewed in Kohler and Grant14). Therefore, a relationship between tPA or PAI-1 levels and stroke is subject to confounding by such factors.14

Until recently, PAI-1 was considered as a potentially harmful factor in stroke etiology because PAI-1 was best known for its antifibrinolytic properties.14 New insights from transgenic mice models show that the involvement of PAI-1 in stroke is more complicated because PAI-1 is involved in both harmful and protective steps in arterial disease etiology.15–19 An important protective function of PAI-1 is the inhibition of the activation of matrix-degrading enzymes in the atherosclerotic plaque, thereby preventing cardiac rupture followed by an ischemic infarction.18 Furthermore, PAI-1 is necessary to protect against tPA, which may cause local damage in the neurological tissue after an ischemic stroke.15

In conclusion, 8 independent studies observed that genetic make-up for increased PAI-1 expression protects against stroke.1–8 Those reproducible genetic associations can be considered as causal evidence that genetic make-up for increased PAI-1 expression protects against stroke because genotype is not subject to confounding and is not a consequence of stroke. The protective involvement of PAI-1 in stroke needs to be investigated further, but the properties of PAI-1 to prevent plaque rupture and protect against neurological damage after an ischemic infarction are both plausible pathways.


*    References
up arrowTop
 *References
 

  1. Hoekstra T, Geleijnse JM, Kluft C, Giltay EJ, Kok FJ, Schouten EG. 4G/4G genotype of PAI-1 gene is associated with reduced risk of stroke in elderly Stroke. . 2003; 34: 2822–2829.[Abstract/Free Full Text]
  2. Catto AJ, Carter AM, Stickland M, et al. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and levels in subjects with cerebrovascular disease. Thromb Haemost. 1997; 77: 730–734.[Medline] [Order article via Infotrieve]
  3. Heijmans BT, Westendorp RG, Knook DL, et al. Angiotensin I-converting enzyme and plasminogen activator inhibitor-1 gene variants: risk of mortality and fatal cardiovascular disease in an elderly population-based cohort. J Am Coll Cardiol. 1999; 34: 1176–1183.[Abstract/Free Full Text]
  4. Roest M, van der Schouw YT, Banga JD, et al. Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation. 2000; 101: 67–70.[Abstract/Free Full Text]
  5. Elbaz A, Cambien F, Amarenco P. Plasminogen activator inhibitor genotype and brain infarction. Circulation. 2001; 103: E13–E14.[Medline] [Order article via Infotrieve]
  6. Endler G, Lalouschek W, Exner M, et al. The 4G/4G genotype at nucleotide position -675 in the promotor region of the plasminogen activator inhibitor 1 (PAI-1) gene is less frequent in young patients with minor stroke than in controls. Br J Haematol. 2000; 110: 469–471.[CrossRef][Medline] [Order article via Infotrieve]
  7. Hindorff LA, Schwartz SM, Siscovick DS, et al. The association of PAI-1 promoter 4G/5G insertion/deletion polymorphism with myocardial infarction and stroke in young women. J Cardiovasc Risk. 2002; 9: 131–137.[CrossRef][Medline] [Order article via Infotrieve]
  8. Petrovic D, Milanez T, Kobal J, et al. Prothrombotic gene polymorphisms and atherothrombotic cerebral infarction. Acta Neurol Scand. 2003; 108: 109–113.[CrossRef][Medline] [Order article via Infotrieve]
  9. Eriksson P, Kallin B, ’t Hooft FM, et al. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A. 1995; 92: 1851–1855.[Abstract/Free Full Text]
  10. Clayton D, McKeigue PM. Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet. 2001; 358: 1356–1360.[CrossRef][Medline] [Order article via Infotrieve]
  11. Ridker PM, Hennekens CH, Stampfer MJ, et al. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet. 1994; 343: 940–943.[CrossRef][Medline] [Order article via Infotrieve]
  12. Smith FB, Lee AJ, Fowkes FG, et al. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol. 1997; 17: 3321–3325.[Abstract/Free Full Text]
  13. Johansson L, Jansson JH, Boman K, et al. Tissue plasminogen activator, plasminogen activator inhibitor-1, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex as risk factors for the development of a first stroke. Stroke. 2000; 31: 26–32.[Abstract/Free Full Text]
  14. Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med. 2000; 342: 1792–1801.[Free Full Text]
  15. Strickland S. Tissue plasminogen activator in nervous system function and dysfunction. Thromb Haemost. 2001; 86: 138–143.[Medline] [Order article via Infotrieve]
  16. Eitzman DT, Westrick RJ, Xu Z, et al. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood. 2000; 96: 4212–4215.[Abstract/Free Full Text]
  17. Luttun A, Lupu F, Storkebaum E, et al. Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2002; 22: 499–505.[Abstract/Free Full Text]
  18. Heymans S, Luttun A, Nuyens D, et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med. 1999; 5: 1135–1142.[CrossRef][Medline] [Order article via Infotrieve]
  19. de Waard V, Arkenbout EK, Carmeliet P, et al. Plasminogen activator inhibitor 1 and vitronectin protect against stenosis in a murine carotid artery ligation model. Arterioscler Thromb Vasc Biol. 2002; 22: 1978–1983.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 StrokeHome page
P.-G. Wiklund, L. Nilsson, S. N. Ardnor, P. Eriksson, L. Johansson, B. Stegmayr, A. Hamsten, D. Holmberg, and K. Asplund
Plasminogen Activator Inhibitor-1 4G/5G Polymorphism and Risk of Stroke: Replicated Findings in Two Nested Case-Control Studies Based on Independent Cohorts
Stroke, August 1, 2005; 36(8): 1661 - 1665.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
34/12/2828    most recent
01.STR.0000103831.56586.4Fv1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Roest, M.
Right arrow Articles by Banga, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Roest, M.
Right arrow Articles by Banga, J. D.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Stroke

Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2003 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.