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1 Davis Heart & Lung Research Institute, Internal Medicine & Biomedical Engineering, Ohio State University, Columbus, Ohio, United States
2 Davis Heart & Lung Research Institute, Internal Medicine & Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States
3 Biophysics Program, The Ohio State University, Columbus, Ohio, United States
4 Davis Heart & Lung Research Institute, Internal Medicine, The Ohio State University, Columbus, Ohio, United States
5 United States; Davis Heart & Lung Research Institute, Internal Medicine, The Ohio State University, Columbus, Ohio, United States
6 Internal Medicine, The Ohio state University, 116A, TMRF, Columbus, Ohio, 43210, United States; Davis Heart & Lung Research Institute, Internal Medicine and Biophysics Program, The Ohio state University, Columbus, Ohio, United States
* To whom correspondence should be addressed. E-mail: Rita.Alevriadou{at}osumc.edu.
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 if the ‘hyperoxic state’ of 21% O2, compared to 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 employed to measure O2 consumption rates of bovine aortic ECs sheared (10 dynes/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 were 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 to 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.
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