Myocardial ischemia-reperfusion enhances transcriptional expression of endothelin-1 and vasoconstrictor ETB receptors via the protein kinase MEK-ERK1/2 signaling pathway in rat
(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)
- author
- Skovsted, Gry Freja
; Kruse, Lars Schack
; Berchtold, Lukas Adrian
; Grell, Anne-Sofie
; Warfvinge, Karin
LU
and Edvinsson, Lars LU
- organization
- publishing date
- 2017-03-01
- 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
- article number
- e0174119
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- pmid:28323857
- pmid:28323857
- wos:000399089000065
- scopus:85015983073
- 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
- 2025-01-07 11:56:58
@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>}}, 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}}, keywords = {{Myocardial ischemia-reperfusion; rat; vasoconstrictor ETB receptors; endothelin 1}}, language = {{eng}}, month = {{03}}, number = {{3}}, publisher = {{Public Library of Science (PLoS)}}, 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}}, doi = {{10.1371/journal.pone.0174119}}, volume = {{12}}, year = {{2017}}, }