Antioxidants & redox signaling, 2008-08, Vol.10 (8), p.1435-1448
2008
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- Autor(en) / Beteiligte
- Titel
- First evidence for a crosstalk between mitochondrial and NADPH oxidase-derived reactive oxygen species in nitroglycerin-triggered vascular dysfunction
- Ist Teil von
- Antioxidants & redox signaling, 2008-08, Vol.10 (8), p.1435-1448
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2008
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Chronic nitroglycerin treatment results in development of nitrate tolerance associated with endothelial dysfunction (ED). We sought to clarify how mitochondria- and NADPH oxidase (Nox)-derived reactive oxygen species (ROS) contribute to nitrate tolerance and nitroglycerin-induced ED. Nitrate tolerance was induced by nitroglycerin infusion in male Wistar rats (100 microg/h/4 day) and in C57/Bl6, p47(phox/) and gp91(phox/) mice (50 microg/h/4 day). Protein and mRNA expression of Nox subunits were unaltered by chronic nitroglycerin treatment. Oxidative stress was determined in vascular rings and mitochondrial fractions of nitroglycerin-treated animals by L-012 enhanced chemiluminescence, revealing a dominant role of mitochondria for nitrate tolerance development. Isometric tension studies revealed that genetic deletion or inhibition (apocynin, 0.35 mg/h/4 day) of Nox improved ED, whereas nitrate tolerance was unaltered. Vice versa, nitrate tolerance was attenuated by co-treatment with the respiratory chain complex I inhibitor rotenone (100 microg/h/4 day) or the mitochondrial permeability transition pore blocker cyclosporine A (50 microg/h/4 day). Both compounds improved ED, suggesting a link between mitochondrial and Nox-derived ROS. Mitochondrial respiratory chain-derived ROS are critical for the development of nitrate tolerance, whereas Nox-derived ROS mediate nitrate tolerance-associated ED. This suggests a crosstalk between mitochondrial and Nox-derived ROS with distinct mechanistic effects and sites for pharmacological intervention.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1523-0864eISSN: 1557-7716DOI: 10.1089/ars.2007.1969Titel-ID: cdi_pubmed_primary_18522491
- Format
- –
- Schlagworte
- Animals, Aorta - drug effects, Aorta - metabolism, Aorta - physiopathology, Blotting, Western, Cell Line, Chromatography, High Pressure Liquid, Cyclosporine - administration & dosage, Cyclosporine - pharmacology, Ethidium - analogs & derivatives, Ethidium - metabolism, Humans, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Mitochondria, Heart - drug effects, Mitochondria, Heart - metabolism, NADPH Oxidases - genetics, NADPH Oxidases - metabolism, Nitroglycerin - administration & dosage, Nitroglycerin - pharmacology, Rats, Rats, Wistar, Reactive Nitrogen Species - metabolism, Reactive Oxygen Species - metabolism, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger - genetics, RNA, Messenger - metabolism, Rotenone - administration & dosage, Rotenone - pharmacology, Transfection, Vasoconstriction - drug effects, Vasodilator Agents - administration & dosage, Vasodilator Agents - pharmacology