The Journal of Experimental Medicine
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Published online 11 December 2000.
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© The Rockefeller University Press, 0022-1007/2000/12/1731/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 12, December 18, 2000 1731-1744

Original Article

Enhanced Peroxynitrite Formation Is Associated with Vascular Aging

Bernd van der Looa,b, Ralf Labuggerb, Jeremy N. Skepperc, Markus Bachschmidd, Juliane Kiloa,b, Janet M. Powellc, Miriam Palacios-Callendere, Jorge D. Erusalimskye, Thomas Quaschningb, Tadeusz Malinskif, Daniel Gygib, Volker Ullrichd, and Thomas F. Lüschera,b
a Division of Cardiology, University Hospital, 8091 Zurich, Switzerland
b Division of Cardiovascular Research, Institute of Physiology, University Zurich-Irchel, 8057 Zurich, Switzerland
c Multi-Imaging Centre, University of Cambridge, Cambridge CB2 3DY, United Kingdom
d Department of Biology, University of Konstanz, 78434 Konstanz, Germany
e Wolfson Institute for Biomedical Research and the Department of Medicine, University College London, London WC1E 6JJ, United Kingdom
f Department of Chemistry, Institute of Biotechnology, Oakland University, Rochester, Michigan 48309

Correspondence to: Thomas F. Lüscher, University Hospital Zurich, Cardiology, Raemistrasse 100, 8091 Zurich, Switzerland. Tel:41-1-255-2121 Fax:41-1-255-4251 E-mail:cardiotfl{at}gmx.ch.

Vascular aging is mainly characterized by endothelial dysfunction. We found decreased free nitric oxide (NO) levels in aged rat aortas, in conjunction with a sevenfold higher expression and activity of endothelial NO synthase (eNOS). This is shown to be a consequence of age-associated enhanced superoxide (·O2-) production with concomitant quenching of NO by the formation of peroxynitrite leading to nitrotyrosilation of mitochondrial manganese superoxide dismutase (MnSOD), a molecular footprint of increased peroxynitrite levels, which also increased with age. Thus, vascular aging appears to be initiated by augmented ·O2- release, trapping of vasorelaxant NO, and subsequent peroxynitrite formation, followed by the nitration and inhibition of MnSOD. Increased eNOS expression and activity is a compensatory, but eventually futile, mechanism to counter regulate the loss of NO. The ultrastructural distribution of 3-nitrotyrosyl suggests that mitochondrial dysfunction plays a major role in the vascular aging process.

Key Words: vascular aging, superoxide, nitric oxide, 3-nitrotyrosine, vascular endothelium


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