Enhanced peroxynitrite formation is associated with vascular aging.
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 (.O(2)(-)) 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.O(2)(-) 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.
van der Loo
B
B
Division of Cardiology, University Hospital, 8091 Zurich, Switzerland.
Labugger
R
R
Skepper
J N
JN
Bachschmid
M
M
Kilo
J
J
Powell
J M
JM
Palacios-Callender
M
M
Erusalimsky
J D
JD
Quaschning
T
T
Malinski
T
T
Gygi
D
D
Ullrich
V
V
Lüscher
T F
TF
D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D001835:Body Weight; D000001:Calcimycin / Q000494:pharmacology; D016922:Cellular Senescence / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004790:Enzyme Induction; D006439:Hemodynamics; D008297:Male; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D009566:Nitrates; D013481:Superoxides; D009599:Nitroprusside; C039642:peroxynitric acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D000001:Calcimycin; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D000109:Acetylcholine