Evidence for an age-related attenuation of cerebral microvascular antioxidant response to oxidative stress.
Effects of aging and oxidative stress were studied in cerebral microvessels and microvessel-depleted brain from 6-, 18-, and 24-month-old C57Bl/6J mice exposed to normoxia, 24 or 48 h hyperoxia, or 24 h hyperoxia followed by 24 h normoxia. Microvessels lacked smooth muscle and consisted predominantly of endothelium. Following exposure and isolation of microvessel and parenchymal proteins, Western blot analysis was performed for detection of cytosolic thioredoxin 1 (TRx 1) and mitochondrial thioredoxin 2 (TRx 2), protein carbonyl, and mitochondrial superoxide dismutase (MnSOD). Both microvessel and parenchymal TRx 1 levels were increased by hyperoxia; however, the microvascular response was limited and delayed in comparison to that of the parenchymal fraction. Whereas TRx 2 levels in microvessels were increased in older mice, irrespective of exposure condition, hyperoxia per se had little or no apparent effect. Parenchymal cells showed no age-related increase in TRx 2 level under normoxic conditions, but showed increased levels following hyperoxia. Microvessel MnSOD was lower than that in parenchymal cells, but increased with age under normoxia, and also was correlated with the duration of hyperoxia. Although hyperoxia augmented MnSOD levels in young (6 months) and middle-aged (18 months) animals, the response was less pronounced in microvessels from senescent, 24-month-old mice. Unlike microvessels, which showed a sustained age-related increase in MnSOD level under each exposure condition, parenchymal cells from normoxic mice showed no increase, and hyperoxia-induced elevations declined with prolonged 48 h exposure. These results indicate that the microvessel endothelium is (1) subjected to a more intense oxidative environment than neurons and glia and (2) is limited by aging in its ability to respond to oxidative insult.
Williams
W M
WM
Laboratory of Biochemistry, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD., USA. wmw5@case.edu
Chung
Y W
YW
D000375:Aging; D000818:Animals; D001784:Blood Gas Analysis; D015153:Blotting, Western; D001923:Brain Chemistry; D002469:Cell Separation; D003600:Cytosol / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000378:metabolism; D013687:Telencephalon / Q000098:blood supply* / Q000737:chemistry / Q000166:cytology; D013879:Thioredoxins / Q000032:analysis / Q000378:metabolism; D013997:Time Factors
D008565:Membrane Proteins; C516112:Txn2 protein, mouse; C504767:Txnl1 protein, mouse; D013879:Thioredoxins; D013482:Superoxide Dismutase