(Circulation. 1999;100:533-540.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Adenovirus-Mediated Overexpression of Tissue Inhibitor of Metalloproteinase-1 Reduces Atherosclerotic Lesions in Apolipoprotein E–Deficient Mice
From Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 321 "Lipoproteins and Atherogenesis," Hôpital de la Pitié-Salpétrière, Paris, France (M.R., P.L., M.M., P.M.L., C.D., M.J.C.); Rhône Poulenc-RORER, Département de Cardiologie, 94403 Vitry sur Seine, France (N.D., F.E., J.M.C.); and Laboratoire mixte Rhône-Poulenc-RORER/CNRS C9923, Génétique Moléculaire de la Neurotransmission et des Processus Dégénératifs, CERVI, Hôpital de la Pitié-Salpêtrière, Paris, France (P.H.).
Correspondence to M. Rouis, PhD, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 321 "Lipoproteins and Atherogenesis" Hôpital de la Pitié-Salpétrière, 83 Bd de l'Hôpital, 75651 Paris Cedex 13, France. E-mail rouis{at}infobiogen.fr
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.
Methods and Results—Infusion of apoE-/- mice fed a
lipid-rich diet with rAd.RSV.TIMP-1 (1x1011 viral
particles) resulted in high hepatic expression of TIMP-1. At 2
weeks after injection, plasma TIMP-1 levels ranged from 7 to 24 µg/mL
(mean 14.8±6.8). Marked overexpression of TIMP-1 was transient, with
levels of TIMP-1 decreasing to 2.5 to 8 µg/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.ßGal.
However, rAd.RSV.TIMP-1–infused mice displayed a marked reduction
(
32%; P<0.05) in mean lesion area per section
(512±121 µm2x103; n=12 sections from 4
animals) as compared with rAd.RSV.ßGal-infused mice (750±182
µm2x103; 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 
-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.
Key Words: atherosclerosis • metalloproteinases • apolipoproteins • genes
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