Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model.
Although matrix metalloproteinases (MMPs) are expressed in abundance in arterial aneurysms, their contribution to arterial wall degeneration, dilation, and rupture has not been determined. We investigated MMP function in a rat model of aneurysm associated with arterial dilation, elastin loss, medial invasion by mononuclear inflammatory cells, and MMP upregulation. Rupture was correlated with increased gelatinase B (MMP-9) and activated gelatinase A (MMP-2). Syngeneic rat smooth muscle cells retrovirally transfected with tissue inhibitor of matrix metalloproteinases (TIMP)-1 cDNA (LTSN) or with the vector alone as a control (LXSN) were seeded onto the luminal surface of the vessels. The seeding of LTSN cells resulted in TIMP-1 local overexpression. The seeding with LTSN cells, but not LXSN cells, decreased MMP-9, activated MMP-2 and 28-kD caseinase and elastase activity, preserved elastin in the media, and prevented aneurysmal degeneration and rupture. We conclude that MMP overexpression is responsible for aneurysmal degeneration and rupture in this rat model and that local pharmacological blockade might be a reasonable strategy for controlling the formation of aneurysms in humans.
Allaire
E
E
Service de Chirurgie Vasculaire, Hôpital H. Mondor, 94010 Créteil, France.
Forough
R
R
Clowes
M
M
Starcher
B
B
Clowes
A W
AW
D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology / Q000502:physiology* / Q000637:transplantation; D017544:Aortic Aneurysm, Abdominal / Q000503:physiopathology*; D001019:Aortic Rupture / Q000503:physiopathology* / Q000517:prevention & control; D017364:Collagenases / Q000378:metabolism; D003895:Desmosine / Q000032:analysis; D004549:Elastin / Q000032:analysis; D018093:Gelatinases / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000502:physiology* / Q000637:transplantation; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000096:biosynthesis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis* / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis; D014162:Transfection; D014183:Transplantation, Heterologous
D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D003895:Desmosine; D019716:Tissue Inhibitor of Metalloproteinase-2; D004549:Elastin; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9