From the Department of Surgery, University of Washington, Seattle (D.H.,
R.D.K., M.M.C., A.W.C.), and the University of Texas Health Center at Tyler,
Department of Biochemistry (B.S.). Dr Allaire is currently at the Service de
Chirurgie Vasculaire, Hôpital H. Mondor, 51 Avenue du Maréchal de
Lattre de Tassigny, 94010 Créteil, France.
Correspondence to Alexander W. Clowes, MD, Department of Surgery, University of Washington School of Medicine, 1959 NE Pacific St, HSB Box 356410, Seattle, WA 98195-6410.
Background—Arterial
aneurysms exhibit a loss of elastin and an increase in the
plasminogen activators urokinase
plasminogen activator (u-PA) and tissue
plasminogen activator (t-PA). Because u-PA,
t-PA, and plasmin have a limited proteolytic activity against elastin,
the role of plasminogen activators in the
aneurysmal disease is unclear. To investigate this question, we
overexpressed plasminogen activator
inhibitor-1 (PAI-1), an inhibitor of t-PA and
u-PA, in a rat model of aortic aneurysm.
Methods and Results—Guinea pig–to-rat aortic xenografts were
seeded with syngeneic Fischer 344 rat smooth muscle cells retrovirally
transduced with the rat PAI-1 gene (LPSN group) or the vector alone
(LXSN group). Some grafts were not seeded with cells (NO group).
Western blots showed increased PAI-1 in grafts from the LPSN group
compared with LXSN and NO groups. All grafts in the NO group (n=8) and
40% in the LXSN group ruptured between days 4 and 14. At 4 weeks in
the LXSN group, the remaining unruptured grafts (n=6) were
aneurysmal (diameter increase
Conclusions—The blockade of plasminogen
activators prevents formation of aneurysms and
arterial rupture by inhibiting MMP activation.
© 1998 American Heart Association, Inc.
Basic Science Reports
Prevention of Aneurysm Development and Rupture by Local Overexpression of Plasminogen Activator Inhibitor-1
100%), whereas in the LPSN
group (n=6) none of the grafts had ruptured or were aneurysmal.
Elastin was preserved in the LPSN group. t-PA, the major PA expressed
in the model, was decreased in the LPSN group compared with the other
groups, as determined by zymography. Quantitative zymography showed
decreased levels of two matrix metalloproteinases (MMPs), a 28-kD
caseinase, and activated MMP-9 in the LPSN group.
Key Words: plasminogen activators • genes • metalloproteinases • aneurysm • transplantation
This article has been cited by other articles:
 |
|
 |
|
  J. P. Schwartz, M. Bakhos, A. Patel, S. Botkin, and S. Neragi-Miandoab Repair of aortic arch and the impact of cross-clamping time, New York Heart Association stage, circulatory arrest time, and age on operative outcome Interactive CardioVascular and Thoracic Surgery, June 1, 2008; 7(3): 425 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Senzaki The pathophysiology of coronary artery aneurysms in Kawasaki disease: role of matrix metalloproteinases Arch. Dis. Child., October 1, 2006; 91(10): 847 - 851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Choke, M. M. Thompson, J. Dawson, W. R. W. Wilson, S. Sayed, I. M. Loftus, and G. W. Cockerill Abdominal Aortic Aneurysm Rupture Is Associated With Increased Medial Neovascularization and Overexpression of Proangiogenic Cytokines Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 2077 - 2082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Touat, V. Ollivier, J. Dai, M.-G. Huisse, A. Bezeaud, U. Sebbag, T. Palombi, P. Rossignol, O. Meilhac, M.-C. Guillin, et al. Renewal of Mural Thrombus Releases Plasma Markers and Is Involved in Aortic Abdominal Aneurysm Evolution Am. J. Pathol., March 1, 2006; 168(3): 1022 - 1030. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dai, F. Losy, A.-M. Guinault, C. Pages, I. Anegon, P. Desgranges, J.-P. Becquemin, and E. Allaire Overexpression of Transforming Growth Factor-{beta}1 Stabilizes Already-Formed Aortic Aneurysms: A First Approach to Induction of Functional Healing by Endovascular Gene Therapy Circulation, August 16, 2005; 112(7): 1008 - 1015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Garcia-Touchard, T. D. Henry, G. Sangiorgi, L. G. Spagnoli, A. Mauriello, C. Conover, and R. S. Schwartz Extracellular Proteases in Atherosclerosis and Restenosis Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1119 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Yasmin, S. Wallace, C. M. McEniery, Z. Dakham, P. Pusalkar, K. Maki-Petaja, M. J. Ashby, J. R. Cockcroft, and I. B. Wilkinson Matrix Metalloproteinase-9 (MMP-9), MMP-2, and Serum Elastase Activity Are Associated With Systolic Hypertension and Arterial Stiffness Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 372 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Ribourtout and J. Raymond Gene Therapy and Endovascular Treatment of Intracranial Aneurysms Stroke, March 1, 2004; 35(3): 786 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. D Defawe, A. Colige, C. A Lambert, C. Munaut, P. Delvenne, C. M Lapiere, R. Limet, B. V Nusgens, and N. Sakalihasan TIMP-2 and PAI-1 mRNA levels are lower in aneurysmal as compared to athero-occlusive abdominal aortas Cardiovasc Res, October 15, 2003; 60(1): 205 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Mulligan-Kehoe, H. K. Kleinman, M. Drinane, R. J. Wagner, C. Wieland, and R. J. Powell A Truncated Plasminogen Activator Inhibitor-1 Protein Blocks the Availability of Heparin-binding Vascular Endothelial Growth Factor A Isoforms J. Biol. Chem., December 6, 2002; 277(50): 49077 - 49089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
|
|
|
|
|
|
F. J. Miller Jr, W. J. Sharp, X. Fang, L. W. Oberley, T. D. Oberley, and N. L. Weintraub Oxidative Stress in Human Abdominal Aortic Aneurysms: A Potential Mediator of Aneurysmal Remodeling Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 560 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Saito, N. Zempo, A. Yamashita, H. Takenaka, K. Fujioka, and K. Esato Matrix Metalloproteinase Expressions in Arteriosclerotic Aneurysmal Disease Vascular and Endovascular Surgery, January 1, 2002; 36(1): 1 - 7. [Abstract] [PDF]
|
|
|
|
|
|
J.-B. Michel Contrasting Outcomes of Atheroma Evolution: Intimal Accumulation Versus Medial Destruction Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1389 - 1392. [Full Text] [PDF]
|
|
|
|
|
|
J. Silence, F. Lupu, D. Collen, and H. R. Lijnen Persistence of Atherosclerotic Plaque but Reduced Aneurysm Formation in Mice With Stromelysin-1 (MMP-3) Gene Inactivation Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1440 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Senzaki, S. Masutani, J. Kobayashi, T. Kobayashi, H. Nakano, H. Nagasaka, N. Sasaki, H. Asano, S. Kyo, and Y. Yokote Circulating Matrix Metalloproteinases and Their Inhibitors in Patients with Kawasaki Disease Circulation, August 21, 2001; 104(8): 860 - 863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. W. Miller, E. Dai, P. Nash, L. Liu, C. Icton, D. Klironomos, L. Fan, P. N. Nation, R. Zhong, G. McFadden, et al. Inhibition of Transplant Vasculopathy in a Rat Aortic Allograft Model After Infusion of Anti-Inflammatory Viral Serpin Circulation, April 4, 2000; 101(13): 1598 - 1605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lopez, F. Peiretti, B. Bonardo, I. Juhan-Vague, and G. Nalbone Tumor Necrosis Factor alpha Up-regulates in an Autocrine Manner the Synthesis of Plasminogen Activator Inhibitor Type-1 during Induction of Monocytic Differentiation of Human HL-60 Leukemia Cells J. Biol. Chem., February 4, 2000; 275(5): 3081 - 3087. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. Loftus, A. R. Naylor, S. Goodall, M. Crowther, L. Jones, P. R. F. Bell, and M. M. Thompson Increased Matrix Metalloproteinase-9 Activity in Unstable Carotid Plaques : A Potential Role in Acute Plaque Disruption Stroke, January 1, 2000; 31(1): 40 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Raymond, A. C. Desfaits, D. Roy, and J. P. Muizelaar Fibrinogen and Vascular Smooth Muscle Cell Grafts Promote Healing of Experimental Aneurysms Treated by Embolization • Editorial Comment Stroke, August 1, 1999; 30(8): 1657 - 1664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. P. Rohde, L. H. Arroyo, N. Rifai, M. A. Creager, P. Libby, P. M. Ridker, and R. T. Lee Plasma Concentrations of Interleukin-6 and Abdominal Aortic Diameter Among Subjects Without Aortic Dilatation Arterioscler. Thromb. Vasc. Biol., July 1, 1999; 19(7): 1695 - 1699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Sukhova, U. Schonbeck, E. Rabkin, F. J. Schoen, A. R. Poole, R. C. Billinghurst, and P. Libby Evidence for Increased Collagenolysis by Interstitial Collagenases-1 and -3 in Vulnerable Human Atheromatous Plaques Circulation, May 18, 1999; 99(19): 2503 - 2509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.J. Davies Aortic Aneurysm Formation : Lessons From Human Studies and Experimental Models Circulation, July 21, 1998; 98(3): 193 - 195. [Full Text] [PDF]
|
|
|
|
|
|
M. J. Mulligan-Kehoe, R. Wagner, C. Wieland, and R. Powell A Truncated Plasminogen Activator Inhibitor-1 Protein Induces and Inhibits Angiostatin (Kringles 1-3), a Plasminogen Cleavage Product J. Biol. Chem., March 9, 2001; 276(11): 8588 - 8596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Miller Jr, W. J. Sharp, X. Fang, L. W. Oberley, T. D. Oberley, and N. L. Weintraub Oxidative Stress in Human Abdominal Aortic Aneurysms: A Potential Mediator of Aneurysmal Remodeling Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 560 - 565. [Abstract] [Full Text] [PDF]
|
|