Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase
Proline-rich tyrosine kinase 2 (PYK2) can be activated by angiotensin II (Ang II) and reactive oxygen species. We report that in endothelial cells, Ang II enhances the tyrosine phosphorylation of endothelial NO synthase (eNOS) in an AT1-, H2O2-, and PYK2-dependent manner. Low concentrations (1–100 µmol/liter) of H2O2 stimulated the phosphorylation of eNOS Tyr657 without affecting that of Ser1177, and attenuated basal and agonist-induced NO production. In isolated mouse aortae, 30 µmol/liter H2O2 induced phosphorylation of eNOS on Tyr657 and impaired acetylcholine-induced relaxation. Endothelial overexpression of a dominant-negative PYK2 mutant protected against H2O2-induced endothelial dysfunction. Correspondingly, carotid arteries from eNOS–/– mice overexpressing the nonphosphorylatable eNOS Y657F mutant were also protected against H2O2. In vivo, 3 wk of treatment with Ang II considerably increased levels of Tyr657-phosphorylated eNOS in the aortae of wild-type but not Nox2y/– mice, and this was again associated with a clear impairment in endothelium-dependent vasodilatation in the wild-type but not in the Nox2y/– mice. Collectively, endothelial PYK2 activation by Ang II and H2O2 causes the phosphorylation of eNOS on Tyr657, attenuating NO production and endothelium-dependent vasodilatation. This mechanism may contribute to the endothelial dysfunction observed in cardiovascular diseases associated with increased activity of the renin–angiotensin system and elevated redox stress.
|Author:||Annemarieke E. Loot, Judith G. Schreiber, Beate Fißlthaler, Ingrid Fleming|
|Parent Title (English):||Journal of experimental medicine|
|Publisher:||Rockefeller Univ. Press|
|Place of publication:||New York, NY|
|Date of Publication (online):||25.05.2010|
|Year of first Publication:||2009|
|Publishing Institution:||Univ.-Bibliothek Frankfurt am Main|
|Source:||The Journal of Experimental Medicine, Vol. 206, No. 13, 2889-2896 ; http://jem.rupress.org/cgi/content/abstract/206/13/2889|
|Dewey Decimal Classification:||610 Medizin und Gesundheit|
Originally published at http://jem.rupress.org/ on Nov 23 2009 ; © 2009 Loot et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
|Licence (German):||Creative Commons - Namensnennung-Keine kommerzielle Nutzung-Weitergabe unter gleichen Bedingungen|