Enhanced Peroxynitrite Formation Is Associated with Vascular Aging

doi:10.1084/jem.192.12.1731

Published online 18 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 Loo^a^,b, Ralf Labugger^b, Jeremy N. Skepper^c, Markus Bachschmid^d, Juliane Kilo^a^,b, Janet M. Powell^c, Miriam Palacios-Callender^e, Jorge D. Erusalimsky^e, Thomas Quaschning^b, Tadeusz Malinski^f, Daniel Gygi^b, Volker Ullrich^d, and Thomas F. Lüscher^a^,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
University Hospital Zurich, Cardiology, Raemistrasse 100, 8091 Zurich, Switzerland.41-1-255-425141-1-255-2121

cardiotfl{at}gmx.ch

Vascular aging is mainly characterized by endothelial dysfunction.We found decreased free nitric oxide (NO) levels in aged rataortas, in conjunction with a sevenfold higher expression andactivity of endothelial NO synthase (eNOS). This is shown tobe a consequence of age-associated enhanced superoxide (·O₂^–)production with concomitant quenching of NO by the formationof peroxynitrite leading to nitrotyrosilation of mitochondrialmanganese superoxide dismutase (MnSOD), a molecular footprintof increased peroxynitrite levels, which also increased withage. Thus, vascular aging appears to be initiated by augmented·O₂^– release, trapping of vasorelaxant NO, andsubsequent peroxynitrite formation, followed by the nitrationand inhibition of MnSOD. Increased eNOS expression and activityis a compensatory, but eventually futile, mechanism to counterregulate the loss of NO. The ultrastructural distribution of3-nitrotyrosyl suggests that mitochondrial dysfunction playsa major role in the vascular aging process.

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

T. Malinski's present address is the Department of Chemistryand Biochemistry, Ohio University, Athens, OH 45701.

Abbreviations used in this paper: eNOS, endothelial NOS; iNOS,inducible NOS; MnSOD, manganese superoxide dismutase; NO, nitricoxide; NOS, NO synthase; SNP, sodium nitroprusside; TBS, Tris-bufferedsaline.

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