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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1901.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Genetic Backgrounds but Not Sizes of Atherosclerotic Lesions Determine Medial Destruction in the Aortic Root of Apolipoprotein E–Deficient Mice

Weibin Shi; Morry D. Brown; Xuping Wang; Jack Wong; David F. Kallmes; Alan H. Matsumoto; Gregory A. Helm; Thomas A. Drake; Aldons J. Lusis

From the Departments of Radiology (W.S., M.D.B., D.F.K., A.H.M.) and Neurosurgery (G.A.H.), and the Cardiovascular Research Center (W.S., M.D.B.), University of Virginia, Charlottesville, Va; and the Departments of Medicine and of Microbiology, Immunology, and Molecular Genetics (X.W., J.W., A.J.L.) and of Pathology (T.A.D.), University of California, Los Angeles.

Correspondence to Weibin Shi, MD, PhD, University of Virginia, Department of Radiology, Box 801339, Room 1171 MR4, 409 Lane Rd, Charlottesville, VA 22908. E-mail ws4v{at}virginia.edu or Aldons J. Lusis, PhD, Department of Medicine, UCLA, 47-123 CHS, Los Angeles, CA 90095-1679. E-mail jlusis@mednet.ucla.edu

Objective— Destruction of the elastic media is the most striking histologic feature of atherosclerotic aortic aneurysms. Apolipoprotein E–deficient (apoE^-/-) mice fed a Western diet develop advanced atherosclerotic lesions in the aorta. We sought to assess the integrity of atherosclerotic aortic walls in 2 apoE^-/- strains, C57BL/6 (B6) and C3H/HeJ (C3H) that differ markedly in atherosclerosis susceptibility.

Methods and Results— C3H.apoE^-/- mice developed much smaller atherosclerotic lesions than did B6.apoE^-/- mice after being fed a Western diet for 16 weeks, but the C3H.apoE^-/- mice exhibited destruction of the elastic media, including erosion, fragmentation, and focal dilatation beneath plaques. Gelatin and casein zymography showed proteolytic activity of matrix metalloproteinases (MMPs) -9, -2, and -12 in aortic tissues and of MMP-9 and -12 in macrophages from both strains. However, C3H.apoE^-/- mice showed significantly increased MMP-2 and -12 activity in aortas and macrophages compared with those from B6.apoE^-/- mice. MMP-9 activity was comparable in aortic tissues of the 2 strains, but it was significantly higher in macrophages from C3H.apoE^-/- than from B6.apoE^-/- mice.

Conclusions— Data indicate that genetic backgrounds but not sizes of atherosclerotic lesions determine medial destruction in the aortic root of apoE^-/- mice and that an increase in MMP proteolytic activity might contribute to the medial destruction of aortic walls in C3H.apoE^-/- mice.

Key Words: atherosclerosis • genetic predisposition • aortic aneurysms • matrix metalloproteinases

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