Document Detail


Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms.
MedLine Citation:
PMID:  10841523     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Abdominal aortic aneurysms represent a life-threatening condition characterized by chronic inflammation, destructive remodeling of the extracellular matrix, and increased local expression of matrix metalloproteinases (MMPs). Both 92-kD gelatinase (MMP-9) and macrophage elastase (MMP-12) have been implicated in this disease, but it is not known if either is necessary in aneurysmal degeneration. We show here that transient elastase perfusion of the mouse aorta results in delayed aneurysm development that is temporally associated with transmural mononuclear inflammation, increased local production of several elastolytic MMPs, and progressive destruction of the elastic lamellae. Elastase-induced aneurysmal degeneration was suppressed by treatment with a nonselective MMP inhibitor (doxycycline) and by targeted gene disruption of MMP-9, but not by isolated deficiency of MMP-12. Bone marrow transplantation from wild-type mice prevented the aneurysm-resistant phenotype in MMP-9-deficient animals, and wild-type mice acquired aneurysm resistance after transplantation from MMP-9-deficient donors. These results demonstrate that inflammatory cell expression of MMP-9 plays a critical role in an experimental model of aortic aneurysm disease, suggesting that therapeutic strategies targeting MMP-9 may limit the growth of small abdominal aortic aneurysms.
Authors:
R Pyo; J K Lee; J M Shipley; J A Curci; D Mao; S J Ziporin; T L Ennis; S D Shapiro; R M Senior; R W Thompson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  105     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2000 Jun 
Date Detail:
Created Date:  2000-08-24     Completed Date:  2000-08-24     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1641-9     Citation Subset:  AIM; IM    
Affiliation:
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, Wohl Hospital, St. Louis, Missouri 63110, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aortic Aneurysm, Abdominal / etiology,  prevention & control*
Bone Marrow Transplantation
Doxycycline / pharmacology
Gene Targeting
Matrix Metalloproteinase 9 / genetics,  physiology*
Mice
Pancreatic Elastase / physiology
Grant Support
ID/Acronym/Agency:
HL-29594/HL/NHLBI NIH HHS; HL-47328/HL/NHLBI NIH HHS; HL-56701/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
564-25-0/Doxycycline; EC 3.4.21.36/Pancreatic Elastase; EC 3.4.24.35/Matrix Metalloproteinase 9
Comments/Corrections
Comment In:
J Clin Invest. 2000 Jun;105(11):1519-20   [PMID:  10841508 ]

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