Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 295, Issue 1, Pages C180-C191Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00549.2007
Keywords
shear stress; endothelium; mitochondria; reactive oxygen species
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Funding
- NHLBI NIH HHS [HL 91417, HL 63744, HL 38324, HL 65608, HL 78796] Funding Source: Medline
- NIBIB NIH HHS [EB 04658] Funding Source: Medline
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Cultured vascular endothelial cell (EC) exposure to steady laminar shear stress results in peroxynitrite (ONOO-) formation intramitochondrially and inactivation of the electron transport chain. We examined whether the hyperoxic state of 21% O-2, compared with more physiological O-2 tensions (PO2), increases the shear-induced nitric oxide ( NO) synthesis and mitochondrial superoxide (O-2(center dot-)) generation leading to ONOO- formation and suppression of respiration. Electron paramagnetic resonance oximetry was used to measure O-2 consumption rates of bovine aortic ECs sheared (10 dyn/cm(2), 30 min) at 5%, 10%, or 21% O-2 or left static at 5% or 21% O2. Respiration was inhibited to a greater extent when ECs were sheared at 21% O-2 than at lower PO2 or left static at different PO2. Flow in the presence of an endothelial NO synthase (eNOS) inhibitor or a ONOO- scavenger abolished the inhibitory effect. EC transfection with an adenovirus that expresses manganese superoxide dismutase in mitochondria, and not a control virus, blocked the inhibitory effect. Intracellular and mitochondrial O-2(center dot-) production was higher in ECs sheared at 21% than at 5% O-2, as determined by dihydroethidium and MitoSOX red fluorescence, respectively, and the latter was, at least in part, NO-dependent. Accumulation of NO metabolites in media of ECs sheared at 21% O-2 was modestly increased compared with ECs sheared at lower PO2, suggesting that eNOS activity may be higher at 21% O-2. Hence, the hyperoxia of in vitro EC flow studies, via increased NO and mitochondrial O-2(center dot-) production, leads to enhanced ONOO- formation intramitochondrially and suppression of respiration.
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