Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E-deficient mice.
BACKGROUND
To define the role of metalloproteinases (MMPs) in the development of lipid-rich atherosclerotic lesions in relation to the balance between proteolytic and antiproteolytic activities, we investigated the impact of adenovirus-mediated elevation in the circulating levels of human tissue inhibitor of MMP (TIMP-1) in atherosclerosis-susceptible apolipoprotein E-deficient (apoE(-/-)) mice.


RESULTS
Infusion of apoE(-/-) mice fed a lipid-rich diet with rAd.RSV.TIMP-1 (1x10(11) viral particles) resulted in high hepatic expression of TIMP-1. At 2 weeks after injection, plasma TIMP-1 levels ranged from 7 to 24 micrograms/mL (mean 14.8+/-6.8). Marked overexpression of TIMP-1 was transient, with levels of TIMP-1 decreasing to 2.5 to 8 micrograms/mL (mean 4.3+/-2.1) at 4 weeks. Plasma lipid and lipoprotein levels in mice treated with rAd.RSV.TIMP-1 were similar to those treated with rAd.RSV.betaGal. However, rAd.RSV.TIMP-1-infused mice displayed a marked reduction (approximately 32%; P<0.05) in mean lesion area per section (512+/-121 micrometers(2)x10(3); n=12 sections from 4 animals) as compared with rAd.RSV.betaGal-infused mice (750+/-182 micrometers(2)x10(3); n=12 sections from 4 animals). Similarly, marked reduction in macrophage deposition as well as MMP-2, MMP-3, and MMP-13 antigens was observed.


CONCLUSIONS
Histological and immunohistologic analyses of atherosclerotic lesions revealed increases in collagen, elastin, and smooth muscle alpha-actin content in mice treated with rAd.RSV.TIMP-1. These qualitative and quantitative features were the consequence of TIMP-1 infiltration from plasma to arterial intima, as immunohistochemical analyses revealed an abundance of TIMP-1 specifically in lesions of rAd.RSV. TIMP-1-treated mice.
Rouis
M
M
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 321 "Lipoproteins and Atherogenesis," Hôpital de la Pitié-Salpétrière, Paris, France. rouis@infobiogen.fr
Adamy
C
C
Duverger
N
N
Lesnik
P
P
Horellou
P
P
Moreau
M
M
Emmanuel
F
F
Caillaud
J M
JM
Laplaud
P M
PM
Dachet
C
C
Chapman
M J
MJ
D000256:Adenoviridae; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D015854:Up-Regulation
D001057:Apolipoproteins E; D004041:Dietary Fats; D019715:Tissue Inhibitor of Metalloproteinase-1