UZH-Logo

Inhibition of activated ERK1/2 and JNKs improves vascular function in mouse aortae in the absence of nitric oxide


Bhattacharya, I; Damjanović, M; Dominguez, A P; Haas, E (2011). Inhibition of activated ERK1/2 and JNKs improves vascular function in mouse aortae in the absence of nitric oxide. European Journal of Pharmacology, 658(1):22-27.

Abstract

Activation of mitogen-activated protein kinases (MAPKs) is important for vascular contraction. Decreased nitric oxide availability combined with activation of MAPKs contributes to an increase in vascular tone. In this study, we have determined the involvement of extracellular signal-regulated kinases1/2 (ERK1/2) and c-Jun N-terminal kinases (JNKs) in reactivity of mouse aortae in the absence of nitric oxide. Additionally, we have examined the contribution of these kinases to endothelium-dependent and prostaglandin F(2α) (PGF(2α))-induced contractions. Precontracted aortic rings were treated with MAPK/ERK kinase1/2 (MEK1/2) inhibitor U0126 or JNKs inhibitor SP600125 to determine reactivity after inhibition of nitric oxide synthase using organ bath chambers. Additionally, rings were pretreated with or without these inhibitors to assess PGF(2α)- and acetylcholine-induced, endothelium-dependent contractions. Specificity of the inhibitors was evaluated in each aortic ring by determining the phosphorylation levels of ERK1/2 and c-Jun using Bio-Plex™ phospho-protein detection kit. In the absence of nitric oxide both inhibitors caused relaxation, and the dilator response was increased by 2.5-fold using SP600125 in comparison with U0126. Transient endothelium-dependent contractions were blocked by U0126, whereas SP600125 strongly attenuated sustained PGF(2α)-induced contractions. U0126 inhibited only phosphorylation of ERK1/2, while SP600125 at higher concentrations not only inhibited phosphorylation of c-Jun but also ERK1/2 phosphorylation. In conclusion, the present study demonstrates that in aortae inhibition of activated ERK1/2 and JNKs mediates vascular relaxation, even in the absence of nitric oxide. Activation of ERK1/2 contributes predominantly to transient endothelium-dependent contractions while JNKs, possibly synergistically with ERK1/2, leads to sustained PGF(2α)-induced contractions.

Activation of mitogen-activated protein kinases (MAPKs) is important for vascular contraction. Decreased nitric oxide availability combined with activation of MAPKs contributes to an increase in vascular tone. In this study, we have determined the involvement of extracellular signal-regulated kinases1/2 (ERK1/2) and c-Jun N-terminal kinases (JNKs) in reactivity of mouse aortae in the absence of nitric oxide. Additionally, we have examined the contribution of these kinases to endothelium-dependent and prostaglandin F(2α) (PGF(2α))-induced contractions. Precontracted aortic rings were treated with MAPK/ERK kinase1/2 (MEK1/2) inhibitor U0126 or JNKs inhibitor SP600125 to determine reactivity after inhibition of nitric oxide synthase using organ bath chambers. Additionally, rings were pretreated with or without these inhibitors to assess PGF(2α)- and acetylcholine-induced, endothelium-dependent contractions. Specificity of the inhibitors was evaluated in each aortic ring by determining the phosphorylation levels of ERK1/2 and c-Jun using Bio-Plex™ phospho-protein detection kit. In the absence of nitric oxide both inhibitors caused relaxation, and the dilator response was increased by 2.5-fold using SP600125 in comparison with U0126. Transient endothelium-dependent contractions were blocked by U0126, whereas SP600125 strongly attenuated sustained PGF(2α)-induced contractions. U0126 inhibited only phosphorylation of ERK1/2, while SP600125 at higher concentrations not only inhibited phosphorylation of c-Jun but also ERK1/2 phosphorylation. In conclusion, the present study demonstrates that in aortae inhibition of activated ERK1/2 and JNKs mediates vascular relaxation, even in the absence of nitric oxide. Activation of ERK1/2 contributes predominantly to transient endothelium-dependent contractions while JNKs, possibly synergistically with ERK1/2, leads to sustained PGF(2α)-induced contractions.

Citations

3 citations in Web of Science®
4 citations in Scopus®
Google Scholar™

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:26 Feb 2012 13:40
Last Modified:05 Apr 2016 15:32
Publisher:Elsevier
ISSN:0014-2999
Publisher DOI:10.1016/j.ejphar.2010.09.053
PubMed ID:20868664

Download

Full text not available from this repository.View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations