OBJECTIVES: We tested whether in vivo nitroglycerin (NTG) treatment causes tyrosine nitration of prostacyclin synthase (PGI(2)-S), one of the nitration targets of peroxynitrite, and whether this may contribute to nitrate tolerance. BACKGROUND: Long-term NTG therapy causes tolerance secondary to increased vasoconstrictor sensitivity and increased vascular formation of reactive oxygen species. Because NTG releases nitric oxide (NO), NTG-induced stimulation of superoxide production should increase vascular nitrotyrosine levels, compatible with increased formation of peroxynitrite, the reaction product from NO and superoxide. METHODS: New Zealand White rabbits and Wistar rats were treated with NTG (0.4 mg/h for 3 days). Tolerance was assessed with isometric tension studies. Vascular peroxynitrite levels were quantified with luminol-derived chemiluminescence (LDCL) and peroxynitrite scavengers, such as uric acid and ebselen. As a surrogate parameter for the assessment of the activity of cyclic guanosine monophosphate-dependent kinase-I (cGK-I; the final signaling pathway for NO), the phosphorylation of the vasodilator-stimulated phosphoprotein (P-VASP) at serine 239 was analyzed. RESULTS: Nitroglycerin treatment increased LDCL, and the inhibitory effect of uric acid and ebselen on LDCL was augmented in tolerant rings. Immunoprecipitation of 3-nitrotyrosine-containing proteins and immunohistochemistry analysis identified PGI(2)-S as a tyrosine-nitrated protein. Accordingly, conversion of ((14)C)-PGH(2) into 6-keto-PGF(1 alpha) (=PGI(2)-S activity) was strongly inhibited. In vitro incubation of tolerant rings with ebselen and uric acid markedly increased the depressed P-VASP levels and improved NTG sensitivity of the tolerant vasculature. CONCLUSIONS: Nitroglycerin-induced vascular peroxynitrite formation inhibits the activity of PGI(2)-S as well as NO, cGMP, and cGK-I signaling, which may contribute to vascular dysfunction in the setting of tolerance.
OBJECTIVES: We tested whether in vivo nitroglycerin (NTG) treatment causes tyrosine nitration of prostacyclin synthase (PGI(2)-S), one of the nitration targets of peroxynitrite, and whether this may contribute to nitrate tolerance. BACKGROUND: Long-term NTG therapy causes tolerance secondary to increased vasoconstrictor sensitivity and increased vascular formation of reactive oxygen species. Because NTG releases nitric oxide (NO), NTG-induced stimulation of superoxide production should increase vascular nitrotyrosine levels, compatible with increased formation of peroxynitrite, the reaction product from NO and superoxide. METHODS: New Zealand White rabbits and Wistar rats were treated with NTG (0.4 mg/h for 3 days). Tolerance was assessed with isometric tension studies. Vascular peroxynitrite levels were quantified with luminol-derived chemiluminescence (LDCL) and peroxynitrite scavengers, such as uric acid and ebselen. As a surrogate parameter for the assessment of the activity of cyclic guanosine monophosphate-dependent kinase-I (cGK-I; the final signaling pathway for NO), the phosphorylation of the vasodilator-stimulated phosphoprotein (P-VASP) at serine 239 was analyzed. RESULTS:Nitroglycerin treatment increased LDCL, and the inhibitory effect of uric acid and ebselen on LDCL was augmented in tolerant rings. Immunoprecipitation of 3-nitrotyrosine-containing proteins and immunohistochemistry analysis identified PGI(2)-S as a tyrosine-nitrated protein. Accordingly, conversion of ((14)C)-PGH(2) into 6-keto-PGF(1 alpha) (=PGI(2)-S activity) was strongly inhibited. In vitro incubation of tolerant rings with ebselen and uric acid markedly increased the depressed P-VASP levels and improved NTG sensitivity of the tolerant vasculature. CONCLUSIONS:Nitroglycerin-induced vascular peroxynitrite formation inhibits the activity of PGI(2)-S as well as NO, cGMP, and cGK-I signaling, which may contribute to vascular dysfunction in the setting of tolerance.
Authors: Swenja Schuhmacher; Marc Foretz; Maike Knorr; Thomas Jansen; Marcus Hortmann; Philip Wenzel; Matthias Oelze; Andrei L Kleschyov; Andreas Daiber; John F Keaney; Gerhard Wegener; Karl Lackner; Thomas Münzel; Benoit Viollet; Eberhard Schulz Journal: Arterioscler Thromb Vasc Biol Date: 2011-01-04 Impact factor: 8.311
Authors: D Allan Butterfield; Marzia Perluigi; Tanea Reed; Tasneem Muharib; Christopher P Hughes; Renã A S Robinson; Rukhsana Sultana Journal: Antioxid Redox Signal Date: 2012-01-18 Impact factor: 8.401
Authors: Matthias Oelze; Maike Knorr; Richard Schell; Jens Kamuf; Andrea Pautz; Julia Art; Philip Wenzel; Thomas Münzel; Hartmut Kleinert; Andreas Daiber Journal: J Biol Chem Date: 2011-01-20 Impact factor: 5.157
Authors: Andreas Daiber; Sebastian Steven; Alina Weber; Vladimir V Shuvaev; Vladimir R Muzykantov; Ismail Laher; Huige Li; Santiago Lamas; Thomas Münzel Journal: Br J Pharmacol Date: 2016-07-04 Impact factor: 8.739
Authors: Philip Wenzel; Andreas Daiber; Matthias Oelze; Moritz Brandt; Ellen Closs; Jian Xu; Thomas Thum; Johann Bauersachs; Georg Ertl; Ming-Hui Zou; Ulrich Förstermann; Thomas Münzel Journal: Atherosclerosis Date: 2007-12-03 Impact factor: 5.162
Authors: David L Carbone; Katriana A Popichak; Julie A Moreno; Stephen Safe; Ronald B Tjalkens Journal: Mol Pharmacol Date: 2008-10-07 Impact factor: 4.436