Mitochondrial Sources of H 2 O 2 Generation Play a Key Role in Flow-Mediated Dilation in Human Coronary Resistance Arteries
- 19 September 2003
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 93 (6), 573-580
- https://doi.org/10.1161/01.res.0000091261.19387.ae
Abstract
We previously showed that hydrogen peroxide (H2O2) contributes to flow-induced dilation in human coronary resistance arteries (HCRAs); however, the source of this H2O2 is not known. We hypothesized that the H2O2 is derived from superoxide (O2·−) generated by mitochondrial respiration. HCRAs were dissected from right atrial appendages obtained from patients during cardiac surgery and cannulated with micropipettes. H2O2-derived radicals and O2·− were detected by electron spin resonance (ESR) using BMPO as the spin trap and by histofluorescence using hydroethidine (HE, 5 μmol/L) and dichlorodihydrofluorescein (DCFH, 5 μmol/L). Diameter changes to increases in pressure gradients (20 and 100 cm H2O) were examined in the absence and the presence of rotenone (1 μmol/L), myxothiazol (100 nmol/L), cyanide (1 μmol/L), mitochondrial complex I, III, and IV inhibitors, respectively, and apocynin (3 mmol/L), a NADPH oxidase inhibitor. At a pressure gradient of 100 cm H2O, ubisemiquinone and hydroxyl radicals were detected from effluents of vessels. Including superoxide dismutase and catalase in the perfusate reduced the ESR signals. Relative ethidium and DCFH fluorescence intensities in HCRAs exposed to flow were enhanced (1.45±0.15 and 1.57±0.12, respectively compared with no-flow) and were inhibited by rotenone (0.87±0.17 and 0.95±0.07). Videomicroscopic studies showed that rotenone and myxothiazol blocked flow-induced dilation (% max. dilation at 100 cm H2O: rotenone, 74±3% versus 3±13%; myxothiazol, 67±3% versus 28±4%; P2O2 formation, and flow-induced dilation is derived from O2·− originating from mitochondrial respiration.Keywords
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