Abstract
Arterial regions exposed to oscillatory shear (OS) in branched arteries are lesion-prone sites of atherosclerosis, whereas those of laminar shear (LS) are relatively well protected. Here, we examined the hypothesis that OS and LS differentially regulate production of O2- from the endothelial NAD(P)H oxidase, which, in turn, is responsible for their opposite effects on a critical atherogenic event, monocyte adhesion. We used aortic endothelial cells obtained from C57BL/6 (MAE-C57) and p47phox-/- (MAE-p47-/-) mice, which lack a component of NAD(P)H oxidase. O2- production was determined by dihydroethidium staining and an electron spin resonance using an electron spin trap methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine. Chronic exposure (18 h) to an arterial level of OS (+/- 5 dynes/cm2) increased O2- (2-fold) and monocyte adhesion (3-fold) in MAE-C57 cells, whereas chronic LS (15 dynes/cm2, 18 h) significantly decreased both monocyte adhesion and O2- compared with static conditions. In contrast, neither LS nor OS were able to induce O2- production and monocyte adhesion to MAE-p47-/-. Treating MAE-C57 with a cell-permeable superoxide dismutase compound, polyethylene glycol-superoxide dismutase, also inhibited OS-induced monocyte adhesion. In addition, over-expressing p47phox in MAE-p47-/- restored OS-induced O2- production and monocyte adhesion. These results suggest that chronic exposure of endothelial cells to OS stimulates O2- and/or its derivatives produced from p47phox-dependent NAD(P)H oxidase, which, in turn, leads to monocyte adhesion, an early and critical atherogenic event.
Highlights
Over-expressing p47phox in MAE-p47؊/؊ restored oscillatory shear (OS)-induced O2؊ production and monocyte adhesion. These results suggest that chronic exposure of endothelial cells to OS stimulates O2؊ and/or its derivatives produced from p47phox-dependent NAD(P)H oxidase, which, in turn, leads to monocyte adhesion, an early and critical atherogenic event
The endothelial NAD(P)H oxidase is comprised of five major components, namely gp91phox and p22phox in the membrane and p47phox, p67phox, and Rac in the cytosol, and it has been suggested to be the major source of O2Ϫ in these cells [9]. p47phox in endothelial cells has been shown to play an essential role in activation of NAD(P)H oxidase and the production of O2Ϫ [11, 12]
Characterization of MAE-C57 and MAE-p47Ϫ/Ϫ Cells—Genotypes of C57BL/6 and p47phoxϪ/Ϫ mice were confirmed by PCR with genomic DNA obtained from tail tissues using two p47phox-specific primers and neomycin-resistant primers as described [15]
Summary
47291–47298, 2003 Printed in U.S.A. Oscillatory Shear Stress Stimulates Endothelial Production of O2؊ from p47phox-dependent NAD(P)H Oxidases, Leading to Monocyte Adhesion*. Over-expressing p47phox in MAE-p47؊/؊ restored OS-induced O2؊ production and monocyte adhesion These results suggest that chronic exposure of endothelial cells to OS stimulates O2؊ and/or its derivatives produced from p47phox-dependent NAD(P)H oxidase, which, in turn, leads to monocyte adhesion, an early and critical atherogenic event. Shear stress (OS), typically ranging Ϯ 5 dynes/cm (Ϯ indicates changes in flow directions) [1, 2] These disturbed shear regions correspond to “lesion-prone” areas that develop early forms of atherosclerotic lesions [1,2,3]. The endothelial NAD(P)H oxidase is comprised of five major components, namely gp91phox (and/or its homologues) and p22phox in the membrane and p47phox, p67phox, and Rac in the cytosol, and it has been suggested to be the major source of O2Ϫ in these cells [9]. p47phox in endothelial cells has been shown to play an essential role in activation of NAD(P)H oxidase and the production of O2Ϫ [11, 12]
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