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VASCULAR BIOLOGY

Endothelial cell respiration is affected by the oxygen tension during shear exposure: role of mitochondrial peroxynitrite

¹Davis Heart and Lung Research Institute, Department of Internal Medicine, ²Department of Biomedical Engineering, and ³Biophysics Program, The Ohio State University, Columbus, Ohio

Submitted 19 November 2007 ; accepted in final form 9 May 2008

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% O₂, compared with more physiological O₂ tensions (PO₂), increases the shear-induced nitric oxide (NO) synthesis and mitochondrial superoxide (O₂^·–) generation leading to ONOO^– formation and suppression of respiration. Electron paramagnetic resonance oximetry was used to measure O₂ consumption rates of bovine aortic ECs sheared (10 dyn/cm², 30 min) at 5%, 10%, or 21% O₂ or left static at 5% or 21% O₂. Respiration was inhibited to a greater extent when ECs were sheared at 21% O₂ 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 O₂^·– production was higher in ECs sheared at 21% than at 5% O₂, 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% O₂ was modestly increased compared with ECs sheared at lower PO₂, suggesting that eNOS activity may be higher at 21% O₂. Hence, the hyperoxia of in vitro EC flow studies, via increased NO and mitochondrial O₂^·– production, leads to enhanced ONOO^– formation intramitochondrially and suppression of respiration.

shear stress; endothelium; mitochondria; reactive oxygen species