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Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation

Nature Genetics volume 17, pages 439–444 (1997)Cite this article

Abstract

The molecular mechanisms predisposing to atherosclerotic aneurysm formation remain undefined%1,5. Nevertheless, rupture of aortic aneurysms is a major cause of death in Western societies, with few available treatments and poor long-term progno–sis. Indirect evidence suggests that matrix metalloproteinases (MMPs) and plasminogen activators (PAs) are involved in its pathogenesis%1,6–12. MMPs are secreted as inactive zymogens (pro-MMPs), requiring activation in the extracellular compartment%11,13. Plasmin, generated from the zymogen plasminogen by tissue-type plasminogen activator (t-PA) or urokinase-type plas-minogen activator (u-PA; refs 14,15), has been proposed as a pos–sible activator in vitro, but evidence for such a role in vivo is lacking%16,17. Analysis of atherosclerotic aorta in mice with a deficiency of apoliprotein E (Apoe−/− ref. 18), singly or combined with a deficiency of t-PA (Apoe−/−.PIar−/−) or of u-PA (Apoe−/−-iPlair−/−, ref. 19), indicated that deficiency of u-PA protected against media destruction and aneurysm formation, probably by means of reduced plasmin-dependent activation of pro-MMPs. This genetic evidence suggests that plasmin is a pathophysiologically signifi–cant activator of pro-MMPs in vivo and may have implications for the design of therapeutic strategies to prevent aortic-wall destruction by controlling Plau gene function.

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References

  1. Anidjar, S. & Kieffer, E. Pathogenesis of acquired aneurysms of the abdominal aorta. Ann. Vase. Surg. 6, 298–305 (1992).

    Article  CAS  Google Scholar 

  2. Braverman, A.C. Penetrating atherosclerotic ulcers of the aorta. Curr. Opin. Cardiol. 9, 591–597 (1994).

    Article  CAS  Google Scholar 

  3. Macsweeney, ST., Powell, J.T & Greenhalgh, R.M. Pathogenesis of abdominal aortic aneurysm. Br. J. Surg. 81, 935–941 (1994).

    Article  CAS  Google Scholar 

  4. Halloran, B.C. & Baxter, B.T. Pathogenesis of aneurysms. Semin. Vase. Surg. 8, 85–92 (1995).

    CAS  Google Scholar 

  5. Patel, M.I., Hardman, D.T., Fisher, C.M. & Appleberg, M. Current views on the pathogenesis of abdominal aortic aneurysms. J. Am. Coll. Surg. 181, 371–382 (1995).

    CAS  PubMed  Google Scholar 

  6. Libby, P. Molecular basis of the acute coronary syndromes. Circulation 91, 2844–2850 (1995).

    Article  CAS  Google Scholar 

  7. Schneiderman, J. et al. Expression of fibrinolytic genes in atherosclerotic abdominal aortic aneurysm wall: a possible mechanism for aneurysm expansion. J. Clin. Invest. 96, 639–645 (1995).

    Article  CAS  Google Scholar 

  8. Newman, K.M. et al. Cellular localization of matrix metalloproteinases in the abdominal aortic aneurysm wall. J. Vase. Surg. 20, 814–820 (1994).

    Article  CAS  Google Scholar 

  9. Halpert, I. et al. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc. Natl. Acad, Sd. USA 93, 9748–9753 (1996).

    Article  CAS  Google Scholar 

  10. Lupu, F. et al. Plasminogen activator expression in human atherosclerotic lesions. Arteriosder. Thromb. Vase. Biol. 15, 1444–1455 (1995).

    Article  CAS  Google Scholar 

  11. Dollery, CM., McEwan, J.R., & Henney, A.M. Matrix metalloproteinases and cardiovascular disease. Ore. Res. 77, 863–868 (1995).

    CAS  Google Scholar 

  12. Galis, Z.S., Sukhova, G.K., Lark, M.W. & Libby, P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest. 94, 2493–2503 (1994).

    Article  CAS  Google Scholar 

  13. Murphy, G. Matrix metalloproteinases and their inhibitors. Acta Orthop. Scand. (Suppl. 256) 66, 55–60 (1995).

    Article  Google Scholar 

  14. Collen, D. & Lijnen, H.R. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood. 78, 3114–3124 (1991).

  15. Carmeliet, P. & Collen, D. Gene manipulation and transfer of the plasminogen system and coagulation system in mice. Semin. Thromb. Hemostasis 22, 525–542 (1996).

    Article  CAS  Google Scholar 

  16. Murphy, G., Atkinson, S., Ward, R., Gavrilovic, J. & Reynolds, J.J. The role of plasminogen activators in the regulation of connective tissue metalloproteinases. Ann. NY Acad. Sd. 667, 1–12 (1992).

    Article  CAS  Google Scholar 

  17. Eeckhout, Y. & Vaes, G. Further studies on the activation of procollagenase, the latent precursor of bone collagenase. Biochem. J. 166, 21–31 (1977).

    Article  CAS  Google Scholar 

  18. Plump, A.S. et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71, 343–353 (1992).

    Article  CAS  Google Scholar 

  19. Carmeliet, P. et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368, 419–424 (1994).

    Article  CAS  Google Scholar 

  20. Johnston, K.W. et al. Suggested standards for reporting on arterial aneurysms. Subcommittee on Reporting Standards for Arterial Aneurysms, Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery. J. Vase. Surg. 13, 452–458 (1991).

    Article  CAS  Google Scholar 

  21. Shapiro, S.D., Kobayashi, D.K. & Ley, T.J. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J. Biol. Chem. 269, 23824–23829 (1993).

    Google Scholar 

  22. Murphy, G., Cockett, M.D., Ward, R.V. & Docherty, A.J.P. Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan: a quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP). Biochem. J. 277, 277–279 (1991).

    Article  CAS  Google Scholar 

  23. Werb, Z., Banda, M.J. & Jones, P.A. Degradation of connective tissue matrices by macrophages: I. Proteolysis of elastin, glycoproteins, and collagen by proteinases isolated from macrophages. J. Exp. Med. 152, 1340–1357 (1980).

    Article  CAS  Google Scholar 

  24. Coussens, L.M. & Werb, Z. Matrix metalloproteinases and the development of cancer. Chem. Biol. 3, 895–904 (1996).

    Article  CAS  Google Scholar 

  25. Paigen, B., Morrow, A., Holmes, P.A., Mitchell, D. & Williams, R.A. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 68, 231–240 (1987).

    Article  CAS  Google Scholar 

  26. Shipley, J.M., Wesselschmidt, R.L., Kobayashi, O.K., Ley, T.J. & Shapiro, S.D. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Natl. Acad. Sd. USA 93, 3942–3946 (1996).

    Article  CAS  Google Scholar 

  27. Carmeliet, P. et al. Urokinase-type but not tissue-type plasminogen activator mediates arterial neointima formation in mice. Circ. Res. 81, 829–839 (1997).

    Article  CAS  Google Scholar 

  28. Delaisse, J. et al. (Pro)collagenase (matrix metalloproteinase-1) is present in rodent osteoclasts and in the underlying bone-resorbing compartment. J. Cell Sd. 106, 1071–1082 (1993).

  29. Senior, R.M., Connelly, N.L., Cury, J.D., Welgus, H.G. & Campbell, E.J. Elastin degradation by human alveolar macrophages: a prominent role of metalloproteinase activity. Am. Rev. Respir. Dis. 139, 1251–1256 (1989).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. The Centre for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium

    Peter Carmeliet, Lieve Moons, Roger Lijnen, Angela Drew & Désiré Collen

  2. Laboratory of Clinical Chemistry and Pharmacy, KU Leuven, Belgium

    Myriam Baes

  3. Cell Biology Unit, International Institute of Cellular and Molecular Pathology, Louvain University Medical School, Brussels, Belgium

    Vincent Lemaître & Yves Eeckhout

  4. The Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Center, Clayton, Australia

    Peter Tipping & Angela Drew

  5. Jewish Hospital, Washington University School of Medicine, St. Louis, Missouri, USA

    Steve Shapiro

  6. Vascular Biology Laboratory, Thrombosis Research Institute, London, UK

    Florea Lupu

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Carmeliet, P., Moons, L., Lijnen, R. et al. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 17, 439–444 (1997). https://doi.org/10.1038/ng1297-439

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