Skip to main content
SpringerLink
Log in

Impact and mechanism for oxidized and glycated lipoproteins on generation of fibrinolytic regulators from vascular endothelial cells

  • Chapter
Vascular Biochemistry

Abstract

Thrombogenesis depends on the balance between coagulation and fibrinolysis in vasculature. Vascular endothelial cells (EC) synthesize activators and inhibitors for fibrinolysis, tissue and urokinase plasminogen activators (tPA and uPA) and plasminogen activator inhibitor-1 (PAI-1). Increased levels of PAI-1 with various levels of tPA have been frequently found in plasma of patients with coronary heart disease (CHD) or diabetes mellitus (DM). Dyslipidemia is common feature in patients with CHD or DM, which is characterized by elevated levels of total cholesterol, triglycerides, low or very low density lipoproteins (LDL or VLDL) and decreased levels of high density lipoprotein (HDL). LDL and VLDL stimulated the generation of PAI-1 from cultured EC. LDL and lipoprotein(a) [Lp(a)], another lipoprotein risk factor for CHD, reduced the generation of tPA from EC. HDL did not greatly alter the release of PAI-1 from EC. Oxidative modification by copper, ultraviolet or long exposure to EC enhanced the effect of LDL on the generation of PAI-1 and tPA from EC. Glycation amplified the effect of LDL and Lp(a) on the changes in the generation of the fibrinolytic regulators from EC. Treatment with antioxidants or HDL normalized glycated LDL-induced changes in the generation of fibrinolytic regulators from EC. Activation of protein kinase C is required for oxidized LDL or Lp(a)-induced PAI-1 production in EC. VLDL, but not LDL or its oxidized form, stimulated PAI-1 production through the activation of the VLDL-responsive element in the PAI-1 promoter. Plasma levels of fibrinolytic regulators in CHD or DM patients may be normalized by HMG-CoA reductase inhibitors and angiotensin II converting enzyme inhibitors. This review summarizes the up-to-date information on effects, mechanism and management for disorders in EC-derived fibrinolytic regulators induced by modified lipoproteins. (Mol Cell Biochem246:69-74, 2003)

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

Reference

  1. Worthley SG, Osende JI, He1ft G, Badimon JJ, Fuster V: Coronary artery disease: Pathogenesis and acute coronary syndrome. Mt Sinai J Med 68: 167–181, 2001

    PubMed  CAS  Google Scholar 

  2. Badimon L: Atherosclerosis and thrombosis: Lessons from animal models. Thromb Haemost 86: 356–365, 2001

    PubMed  CAS  Google Scholar 

  3. Naruszewicz M, Giroux LM, Davignon J: Oxidative modification of Lp(a) causes changes in the structure and biological properties of Lp(a). Chem Phys Lipids 67: 67–68, 1994

    Google Scholar 

  4. Kobayashi K, Watanabe J, Umeda F, Nawata H: Glycation accelerate the oxidation of low density lipoprotein by copper ions. Endocrine J 42: 461–465, 1995

    Article  CAS  Google Scholar 

  5. Shen GX: Vascular cell-derived fibrinolytic regulators and atherothrombotic vascular disorders. Int J Mol Med 1: 399–408, 1998

    PubMed  CAS  Google Scholar 

  6. Saksela O, Rifkin DB: Cell-associated plasminogen activation: Regulation and physiological functions. Ann Rev Cell Biol 4: 93–126, 1988

    Article  PubMed  CAS  Google Scholar 

  7. Hamsten A, D Faire U, Walldius G, Dahlen G, Szamosi A, Blomback M, Landou C, Wiman B: Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction. Lancet 2: 3–9, 1987

    Article  PubMed  CAS  Google Scholar 

  8. Cortellaro M, Cafrancesco E, Boshetti C, Mussoni L, Ponati MB, Cardillo M, Garbrielli L, Lombard B, Secchia G: Increased fibrin turnover and high PAI-1 antigen as predicator of ischemic event in atherosclerotic patients. The PLAT group. Arterioscler Thromb Vasc Biol 13: 1412–1417, 1993

    Article  CAS  Google Scholar 

  9. Yorimitsu K, Saito T, Toyozaki T, Ishide T, Ohnuma N, Inagaki Y: Immunohistochemical localization of plasminogen activator inhibitor-1 in human coronary atherosclerosis lesions involved in acute myocardial infarction. Heart Vessels 8: 160–162, 1993

    Article  PubMed  CAS  Google Scholar 

  10. Amman V, Nilson A, Stemme S, Risberg B, Rymo L: Expression of plasminogen activator inhibitor-1 mRNA in healthy, atherosclerotic and thrombotic arteries and veins. Thromb Res 74: 487–499, 1994

    Article  Google Scholar 

  11. Geiger M, Binder BR: Plasminogen. Enzyme 40: 149–157, 1988

    CAS  Google Scholar 

  12. Auwerx J, Bouillon R, Collen D, Geboers J: Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. Arteriosclerosis 8: 68–72, 1988

    Article  PubMed  CAS  Google Scholar 

  13. Matsuo T, Kadowaki S, Okada K, Matsuo O: Activity of tissue plasminogen activator and plasminogen activator inhibitor in noninsulindependent diabetes mellitus. J Diabet Complications 4: 119–121, 1990

    Article  PubMed  CAS  Google Scholar 

  14. Gough SC, Rice PJ, McCormack L, Chapman C, Grant PJ: The relationship between plasminogen activator inhibitor-1 and insulin resistance in newly diagnosed type 2 diabetes mellitus. Diabet Med 10: 638–642, 1993

    Article  PubMed  CAS  Google Scholar 

  15. Vicari AM, Vigano-D’Angelo S, Testa S, Comi G Galardi G, Orsi E, D’Angelo A: Normal tissue plasminogen activator and plasminogen activator inhibitor activity in plasma from patients with type 1 diabetes mellitus. Horm Metab Res 24: 516–519, 1992

    Article  PubMed  CAS  Google Scholar 

  16. Ceriello A, Quatraro A, Marchi E, Barbanti M, Giugliano D: Impaired fibrinolytic response to increased thrombin activation in type activation in type 1 diabetes mellitus: Effects of the glycosaminoglycan sulodexide. Diabetes Metab 19: 225–259, 1993

    CAS  Google Scholar 

  17. Carmassi F, Morale M, Puccett R, De-Negre F, Monzani F, Navalesi R, Mariani G: Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res 67: 643–654, 1992

    Article  PubMed  CAS  Google Scholar 

  18. Davi G, Violi F, Catalano I, Giammarresi C, Putignano E, Nicolosi G, Barbagallo M, Notarbartolo A: Increased plasminogen activator inhibitor antigen levels in diabetic patients with stable angina. Blood Coagul Fibrinolysis 2: 41–45, 1991

    Article  PubMed  CAS  Google Scholar 

  19. Nagi K, Mohammed AV, Jain SK, Walji S, Yudkin JS: Plasminogen activator inhibitor (PAI-1) activity is elevated in Asian and Caucasian subjects with non-insulin-dependent (type-2) diabetes but not in those with impaired glucose tolerance (IGT) or non-diabetic Asians. Diabet Med 13: 59–64, 1996

    Article  PubMed  CAS  Google Scholar 

  20. Jokl R, Klein RL, Lopes-Virella MF, Colwell JA: Release of platelet plasminogen activator inhibitor 1 in whole blood is increased in patients with type II diabetes. Diabetes Care 18: 1150–115455, 1995

    Article  PubMed  CAS  Google Scholar 

  21. Striko-Rahm A, Wiman B, Hamsten A, Nilsson J: P Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis 10: 1067–1073, 1990

    Article  Google Scholar 

  22. Tremoli E, Camera M, Maderna P, Sironi L, Prati L, Colli S, Piovella F, Bernini F, Corsini A, Mussoni: Increased synthesis of plasminogen activator inhibitor-1 by cultured human endothelial cells exposed to native and modified LDLs: An LDL receptor-independent phenomenon. Arterioscler Thromb 13: 338–346, 1993

    Article  PubMed  CAS  Google Scholar 

  23. Latron Y, Chautan M, Anfosso F, Salessi MC, Lafont H, Juhan-Vague I, : Stimulating effect of oxidized low density lipoprotein on plasminogen activator-1 synthesis by endothelial cells. Arteroscler Thromb 11: 182–189, 1991

    Google Scholar 

  24. Chauton M, Latron Y, Anfosso F, Alessi MC, Lafont H, Juhan-Vague I, Nalbone G, : Phosphatidylinositol turnover during stimulation of plasminogen activator inhibitory secretion induced by oxidized low density lipoproteins in human endothelial cells. J Lipid Res 34: 101–110, 1993

    Google Scholar 

  25. Kugiyama K, Sakamoto T, Ohgushi M, Ogawa H, Horiguchi M, Yasue H: Transferable lipids in oxidized low density lipoprotein stimulate plasminogen activator inhibitory and inhibit tissue plasminogen activator release from endothelial cells. Circ Res 73: 335–343, 1993

    Article  PubMed  CAS  Google Scholar 

  26. Ren S, Man RYK, Angel A, Shen GX: Oxidative modification enhances lipoprotein(a)-induced overproduction of plasminogen activator inhibitory in cultured vascular endothelial cells. Atherosclerosis 128: 1–10, 1997

    Article  PubMed  CAS  Google Scholar 

  27. Etingin OR, Hajjar KA, Harpel PC, Nachman RL: Lipoprotein(a) regulates plasminogen activator inhibitor- I expression in endothelial cells. J Biol Chem 266: 2456–2465, 1991

    Google Scholar 

  28. Festa A, D’ Agostino R Jr, Mykkanen L, Tracy R, Howard B V, Haffner SM: Low-density lipoprotein particle size is inversely related to plasminogen activator inhibitor- 1 levels. The Insulin Resistance Atherosclersis Study. Arterioscler Thromb Vasc Biol 19: 605–610, 1999

    Article  PubMed  CAS  Google Scholar 

  29. Levin EG, Miles LA, Fless GM, Scanu AM, Baynhrna P, Curtiss LK, Plow EF: Lipoproteins inhibits the secretion of tissue plasminogen activator from human endothelial cells. Arterioscler Thromb 14: 43842,1994

    Article  Google Scholar 

  30. Ren S, Shen GX: Impact of antioxidant and HDL on glycated LDLinduced generation of fibrinolytic regulators from vascular endothelial cells. Arterioscler Thromb Vasc Biol 20: 1688–1693, 2000

    Article  PubMed  CAS  Google Scholar 

  31. Beaudeux JL, Therond P, Bonnefont-Rousselot D, Gardes-Albert M, Legrand A, Delattre J, Peynet J: Comparison of the effects of 02*-/H0* free radical-and copper-oxidized LDL or lipoprotein(a) on the endothelial cell release of tissue plasminogen activator and plasminogen activator inhibitory. Life Sci 69: 2371–2382, 2001

    Article  Google Scholar 

  32. Bunn HF, Gabbay KH, Gallo PM: The glycosylation of haemoglobin: Relevance to diabetes mellitus. Science 200: 21–27, 1978

    Article  PubMed  CAS  Google Scholar 

  33. Lyons TJ, Baynes JW, Patrick JS, Colwell JA, Lopes-Virella MF: Glycosylation of low density lipoprotein in patients with type I (insulin-dependent) diabetes: Correlation with other parameters of glycaemic control. Diabetologia 29: 685–689, 1986

    Article  PubMed  CAS  Google Scholar 

  34. Zhang JY, Ren S, Sun DF, Shen, GX: Influence of glycation on LDLinduced generation of fibrinolytic regulators in vascular endothelial cells. Arterioscler Thromb Vase Biol 18: 1140–1148, 1998

    Article  CAS  Google Scholar 

  35. Zhang JY, Ren S, Shen, GX: Glycation amplifies lipoprotein(a)-induced alterations in the generation of fibrinolytic regulators from human vascular endothelial cells. Atherosclerosis 150: 299–308, 2000

    Article  PubMed  CAS  Google Scholar 

  36. Ren S, Lee H, Hu L, Lu L, Shen GX: Impact of diabetes-associated lipoproteins on the generation of fibrinolytic regulators from vascular endothelial cells. J Clin Endocrin Metab 87: 286–291, 2002

    Article  CAS  Google Scholar 

  37. Bosma PJ, van der Berg E, Kooistra T, Siemieniak DR, Slightom JL: Human plasminogen activator inhibitory. Promoter and structural gene nucleotide sequences. J Biol Chem 263: 9129–9141, 1988

    PubMed  CAS  Google Scholar 

  38. Strandberg L, Awrence D, Ny T: The organization of the human-plasminogen-activator-inhibitor 1 gene. Implication on the evolution of the serine-protease inhibitor family. Eur J Biochem 176: 609–616, 1988

    Article  PubMed  CAS  Google Scholar 

  39. Deschemaeker KA, Wyns S, Nelles L, Auwerx J, Ny T, Collen D: Interaction of AP-1, AP-2, and Spl-like proteins with two distinct sites in the upstream regulatory regions of the plasminogen activator inhibitory gene mediates the phorbol 12-myristate 13-acetate response. J Biol Chem 267: 15086–15091, 1992

    Google Scholar 

  40. Westerhausen DR Jr, Hopkins WE, Billadello JJ: Multiple transformation growth factor-O-inducible elements regulate expression of the plasminogen activator inhibitor type-1 gene in Hep G2 cells. J Biol Chem 266: 1092–1100, 1991

    PubMed  CAS  Google Scholar 

  41. Keeton MR, Curriden SA, van Zonneveld AJ, Loskutoff DJ: Identification of regulatory of sequences in the type-1 plasminogen a gene responsive to transformation growth factor-f3. J Biol Chem 266: 23048–23052, 1991

    PubMed  CAS  Google Scholar 

  42. Bruzdzinski CJ, Johnson MR, Goble CA, Winograd SS, Gelenrter TD: Mechanism of glucocorticoid induction of the rat plasminogen activator inhibitory gene in HTC Rat hepatoma cells: Identification of cis-acting regulatory elements. Mol Endocrinol 7: 1169–1177, 1993

    Article  PubMed  CAS  Google Scholar 

  43. Eriksson P, Nilsson L, Karpe F, Hamsten A: Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor- 1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol 18: 20–26, 1998

    Article  CAS  Google Scholar 

  44. Dawson S, Wiman B, Hamsten A, Green F, Humphries SE, Hanney AM: The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitory (gene) respond differently to interleukin-1 in HepG2 cells. J Biol Chem 268: 10739–10745, 1993

    PubMed  CAS  Google Scholar 

  45. Erikson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A: Allele-specific increase in basal transcription of the plasminogen-activator inhibitor- I gene is associated with myocardial infarction. Proc Natl Acad Sci USA 92: 1851–1855, 1995

    Article  Google Scholar 

  46. Margaglione M, Cappucci G, Colaizzo D, Giuliani N, Vecchione G, Grandone E, Pennelli O, Minno GD: The PAI-1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease. Arterioscler Thromb Vasc Biol 8: 152–156,1998.

    Article  Google Scholar 

  47. Ye S, Green FR, Scarabin PY, Nicaud V, Sara 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- I (PAI-1) gene is associated with differences in plasma PAI-I activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost 74: 837–841, 1995

    PubMed  CAS  Google Scholar 

  48. Nilsson L, Banfi C, Diczfalusy U, Tremoli E, Eriksson P: Unsaturated fatty acids increase plasminogen activator inhibitory expression in endothelial cells. Arterioscler Thromb Vasc Biol 18: 1679–1685,1998.

    Article  PubMed  CAS  Google Scholar 

  49. Allison BA, Nilsson L, Karpe F, Hamsten A, Eriksson P: Effects of native, triglyceride-enriched, and oxidatively modified LDL on plasminogen activator inhibitor-1 expression in human endothelial cells. Arterioscler Thromb Vasc Biol 19: 1354–1360, 1999

    Article  PubMed  CAS  Google Scholar 

  50. Lu L, Hu L, Ren S, Shen GX:Oxidized LDL and VLDL stimulates plasminogen activator inhibitory promoter through a mechanism independent from the VLDL-response element Arterloscler Thromb Vasc Biol 21: (abstr) 641, 2001

    Google Scholar 

  51. Ren S, Shatadal S, Shen GX: Protein kinase C-13 mediates lipoprotein-induced generation of PAI-I from vascular endothelial cells. Am J Physiol: Endocrinol Metab 278: E656–E662, 2000

    CAS  Google Scholar 

  52. Lottenuiser K, Wostmann B, Weisser B, Hertfelder Hi, Schmitz U, Vetter H, Dusing R, : Effects of catopril on fibrinolytic function in healthy humans. Eur J Med Res 4: 31–34, 1999

    Google Scholar 

  53. Wright RA, Flapan AD, Alberti KG, Ludlam CA, Fox KA: Effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction. J Am Coll Cardiol 24: 67–73, 1994

    Article  PubMed  CAS  Google Scholar 

  54. Goodfield N-E, Newby DE, Ludlam CA, Flapan AD: Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation 99: 2983–2985, 1999

    Article  PubMed  CAS  Google Scholar 

  55. Li-Saw-Hee FL, Beever DG, Lip GY, : Effect of antihypertensive therapy using enalapril or losartan on haemostatic markers in essential hypertension: A pilot prospective randomized double blind parallel group trial. Int J Cardiol 78: 241–246, 2001

    Article  PubMed  CAS  Google Scholar 

  56. Wada H, Mori Y, Kaneko T, Wakita Y, Nakase T, Minamikawa K, Ohiwa M, Tamaki, Tanigawa M, Kageyma S, : Elevated plasma levels of vascular endothelial cell markers in patients with hypercholesterolemia. Am J Hematol 44: 112–116, 1993

    Article  PubMed  CAS  Google Scholar 

  57. Dhannalingam S, Ludwig S, Ren S, Fenton JW II, Velthius HT, Ofosu FA, Shen G: Simvastatin reduces plasma levels of plasminogen activator inhibitor-1 in patients with type 2 diabetic patients. Can J Diabetes Care 25: (abstr) 194, 2001

    Google Scholar 

  58. Koh KK, Cardillo C, Bui NIN, Hathaway L, Csalo G, Waclawiw MA, Panza JA, Cannon RO III: Vascular effects of estrogen and cholesterol lowering therapies in hypercholesterolemic postmenopausal women. Circulation 99: 3 54–3 60, 1999

    Google Scholar 

  59. Estelles A, Dalmau J, Falco C, Berbel O, Castello R, Espnan F, Aznar J, : Plasma PAI-I levels in obese children-effect of weight loss and influence of PAI-1 promoter 4G/5G gene type. Thromb Haemost 86: 647–652, 2001

    PubMed  CAS  Google Scholar 

  60. Feener EP, Northrup JM, Aiello LP, King GL, : Angiotensin 11 induces plasminogen activator inhibitor-1 and -2 expression in vascular EC and smooth muscle cells. J Clin Invest 95: 1253 -1262, 1995

    Article  Google Scholar 

  61. Lopez S, Peiretti F, Bonardo B, Juhan-Vague I, Nalbone G: Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells. Atherosclerosis 152: 359–366, 2000

    Article  PubMed  CAS  Google Scholar 

  62. Boucier T, Libby P:HMG-COA reductase inhibitors reduce plasminogen activator inhibitors expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol 20: 556–562, 2000

    Google Scholar 

  63. Jenkins Al, Li W, Moller K, Klein RL, Fu MX, Baynes JW, Thorpe SR, Lyons TJ, : Preenrichment of modified low density lipoproteins with alpha tocopherol mitigates adverse effect on cultured retinal capillary cells. Cur Eye Res 19: 137–145, 1999

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Diabetes Research Group, University of Manitoba, Winnipeg, Manitoba, Canada

    Garry X. Shen

Authors
  1. Garry X. Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Research Center, St. Boniface General Hospital, 351 Tache Avenue, Winnipeg, Manitoba, R2H 2A6, Canada

    Peter Zahradka

  2. Institute of Cardiovascular Sciences, St. Boniface General Hospital, 351 Tache Avenue, Winnipeg, Manitoba, R2H 2A6, Canada

    Jeffrey Wigle

  3. Division of Stroke & Vascular Disease, St. Boniface General Hospital Research Center, Canada

    Grant N. Pierce

  4. Faculty of Medicine, University of Manitoba, R2H 2A6, Winnipeg, Manitoba, Canada

    Grant N. Pierce

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Shen, G.X. (2003). Impact and mechanism for oxidized and glycated lipoproteins on generation of fibrinolytic regulators from vascular endothelial cells. In: Zahradka, P., Wigle, J., Pierce, G.N. (eds) Vascular Biochemistry. Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease, vol 41. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0298-2_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0298-2_10

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5010-1

  • Online ISBN: 978-1-4615-0298-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation