Published online before print May 12, 2003, doi: 10.1161/01.HYP.0000073843.56046.45
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(Hypertension. 2003;41:1308.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Aging Increases Aortic MMP-2 Activity and Angiotensin II in Nonhuman Primates
From the National Institute on Aging, Intramural Research Program, Gerontology Research Center (M.W., E.G.L.), National Institutes of Health, Baltimore, Md; the Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School (G.T., K.A., D.E.V., S.F.V.), Newark; and Siconbrec (R.G.R.) and St. Luke’s Hospital (F.F.N.), Manila, Philippines.
Correspondence to Edward G. Lakatta, MD, Laboratory of Cardiovascular Sciences, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr, Baltimore, Md. E-mail lakattae{at}grc.nia.nih.gov
To seek evidence that the nonhuman primate arterial wall, as it ages in the absence of atherosclerosis, exhibits alterations in pathways that are involved in the pathogenesis of experimental atherosclerosis, we assessed aortic matrix metalloproteinase-2 (MMP-2) and its regulators, ie, membrane type-1 of matrix metalloproteinase (MT1-MMP) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and the expression of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and chymase in young (6.4±0.7 years) and old (20.0±1.9 years) male monkeys. With advancing age, (1) the intimal thickness increased 3-fold and contained numerous vascular smooth muscle cells and matrix, but no inflammatory cells; (2) the intimal MMP-2 antibody–staining fraction increased by 80% (P<0.01); (3) in situ zymography showed that MMP-2 activity, mainly confined to the intima, increased 3-fold (P<0.01); (4) the MT1-MMP antibody–staining fraction increased by 150% (P<0.001), but the TIMP-2 antibody–staining fraction did not significantly change; (5) steady levels of the mRNA-staining fraction (via in situ hybridization) for MMP-2 increased 7-fold, for MT1-MMP increased 9-fold, and for TIMP-2 increased 2-fold (all P<0.001); and (6) intimal Ang II and ACE immunofluorescence were increased 5-fold and 5.6-fold, respectively, and colocalized with MMP-2. Thus, age-associated arterial remodeling and the development and progression of experimental atherosclerosis in young animals share common mechanisms, ie, MMP-2 activation and increased Ang II signaling. This might explain, in part, the dramatically exaggerated prevalence and severity of vascular diseases with aging.
Key Words: aging • vasculature • enzymes • angiotensin II • monkeys
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