First evidence for a crosstalk between mitochondrial and NADPH oxidase-derived reactive oxygen species in nitroglycerin-triggered vascular dysfunction

• Published in: Antioxidants & redox signaling Vol. 10; no. 8; p. 1435
• Main Authors: Wenzel, Philip, Mollnau, Hanke, Oelze, Matthias, Schulz, Eberhard, Wickramanayake, Jennifer M Dias, Müller, Johanna, Schuhmacher, Swenja, Hortmann, Marcus, Baldus, Stephan, Gori, Tommaso, Brandes, Ralf P, Münzel, Thomas, Daiber, Andreas
• Format: Journal Article
• Language: English
• Published: United States 01.08.2008
• Subjects: 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
• ISSN: 1557-7716
• DOI: 10.1089/ars.2007.1969

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.