Advanced

Myocardial ischemia-reperfusion enhances transcriptional expression of endothelin-1 and vasoconstrictor ETB receptors via the protein kinase MEK-ERK1/2 signaling pathway in rat

Skovsted, Gry Freja; Kruse, Lars Schack; Berchtold, Lukas Adrian; Grell, Anne-Sofie; Warfvinge, Karin LU and Edvinsson, Lars LU (2017) In PLoS ONE 12(3).
Abstract

Background: Coronary artery remodelling and vasospasm is a complication of acute myocardial ischemia and reperfusion. The underlying mechanisms are complex, but the vasoconstrictor peptide endothelin-1 is suggested to have an important role. This study aimed to determine whether the expression of endothelin-1 and its receptors are regulated in the myocardium and in coronary arteries after experimental ischemia-reperfusion. Furthermore, we evaluated whether treatment with a specific MEK1/2 inhibitor, U0126, modified the expression and function of these proteins. Methods and findings: Sprague-Dawley rats were randomly divided into three groups: sham-operated, ischemiareperfusion with vehicle treatment and ischemia-reperfusion with U0126... (More)

Background: Coronary artery remodelling and vasospasm is a complication of acute myocardial ischemia and reperfusion. The underlying mechanisms are complex, but the vasoconstrictor peptide endothelin-1 is suggested to have an important role. This study aimed to determine whether the expression of endothelin-1 and its receptors are regulated in the myocardium and in coronary arteries after experimental ischemia-reperfusion. Furthermore, we evaluated whether treatment with a specific MEK1/2 inhibitor, U0126, modified the expression and function of these proteins. Methods and findings: Sprague-Dawley rats were randomly divided into three groups: sham-operated, ischemiareperfusion with vehicle treatment and ischemia-reperfusion with U0126 treatment. Ischemia was induced by ligating the left anterior descending coronary artery for 30 minutes followed by reperfusion. U0126 was administered before ischemia and repeated 6 hours after start of reperfusion. The contractile properties of isolated coronary arteries to endothelin-1 and sarafotoxin 6c were evaluated using wire-myography. The gene expression of endothelin-1 and endothelin receptors were measured using qPCR. Distribution and localization of proteins (pERK1/2, prepro-endothelin-1, endothelin-1, and endothelin ETA and ETB receptors) were analysed by Western blot and immunohistochemistry. We found that pERK1/2 was significantly augmented in the ischemic area 3 hours after ischemia-reperfusion; this correlated with increased ETB receptor and ET-1 gene expressions in ischemic myocardium and in coronary arteries. ETB receptor-mediated vasoconstriction was observed to be increased in coronary arteries 24 hours after ischemia-reperfusion. Treatment with U0126 reduced pERK1/2, expression of ET-1 and ETB receptor, and ETB receptor-mediated vasoconstriction. Conclusions: These findings suggest that the MEK-ERK1/2 signaling pathway is important for regulating endothelin-1 and ETB receptors in myocardium and coronary arteries after ischemia-reperfusion in the ischemic region. Inhibition of the MEK-ERK1/2 pathway may provide a novel target for reducing ischemia-reperfusion damage in the heart.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Myocardial ischemia-reperfusion, rat, vasoconstrictor ETB receptors , endothelin 1
in
PLoS ONE
volume
12
issue
3
publisher
Public Library of Science
external identifiers
  • scopus:85015983073
  • pmid:28323857
  • wos:000399089000065
ISSN
1932-6203
DOI
10.1371/journal.pone.0174119
language
English
LU publication?
yes
id
8932fd48-96b6-4a5e-bd37-1cec4846c7e2
date added to LUP
2017-04-24 11:29:24
date last changed
2017-09-18 13:33:02
@article{8932fd48-96b6-4a5e-bd37-1cec4846c7e2,
  abstract     = {<p>Background: Coronary artery remodelling and vasospasm is a complication of acute myocardial ischemia and reperfusion. The underlying mechanisms are complex, but the vasoconstrictor peptide endothelin-1 is suggested to have an important role. This study aimed to determine whether the expression of endothelin-1 and its receptors are regulated in the myocardium and in coronary arteries after experimental ischemia-reperfusion. Furthermore, we evaluated whether treatment with a specific MEK1/2 inhibitor, U0126, modified the expression and function of these proteins. Methods and findings: Sprague-Dawley rats were randomly divided into three groups: sham-operated, ischemiareperfusion with vehicle treatment and ischemia-reperfusion with U0126 treatment. Ischemia was induced by ligating the left anterior descending coronary artery for 30 minutes followed by reperfusion. U0126 was administered before ischemia and repeated 6 hours after start of reperfusion. The contractile properties of isolated coronary arteries to endothelin-1 and sarafotoxin 6c were evaluated using wire-myography. The gene expression of endothelin-1 and endothelin receptors were measured using qPCR. Distribution and localization of proteins (pERK1/2, prepro-endothelin-1, endothelin-1, and endothelin ET<sub>A</sub> and ET<sub>B</sub> receptors) were analysed by Western blot and immunohistochemistry. We found that pERK1/2 was significantly augmented in the ischemic area 3 hours after ischemia-reperfusion; this correlated with increased ET<sub>B</sub> receptor and ET-1 gene expressions in ischemic myocardium and in coronary arteries. ET<sub>B</sub> receptor-mediated vasoconstriction was observed to be increased in coronary arteries 24 hours after ischemia-reperfusion. Treatment with U0126 reduced pERK1/2, expression of ET-1 and ET<sub>B</sub> receptor, and ET<sub>B</sub> receptor-mediated vasoconstriction. Conclusions: These findings suggest that the MEK-ERK1/2 signaling pathway is important for regulating endothelin-1 and ET<sub>B</sub> receptors in myocardium and coronary arteries after ischemia-reperfusion in the ischemic region. Inhibition of the MEK-ERK1/2 pathway may provide a novel target for reducing ischemia-reperfusion damage in the heart.</p>},
  articleno    = {e0174119},
  author       = {Skovsted, Gry Freja and Kruse, Lars Schack and Berchtold, Lukas Adrian and Grell, Anne-Sofie and Warfvinge, Karin and Edvinsson, Lars},
  issn         = {1932-6203},
  keyword      = {Myocardial ischemia-reperfusion,rat,vasoconstrictor ETB receptors ,endothelin 1},
  language     = {eng},
  month        = {03},
  number       = {3},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Myocardial ischemia-reperfusion enhances transcriptional expression of endothelin-1 and vasoconstrictor ET<sub>B</sub> receptors via the protein kinase MEK-ERK1/2 signaling pathway in rat},
  url          = {http://dx.doi.org/10.1371/journal.pone.0174119},
  volume       = {12},
  year         = {2017},
}