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G Protein-Coupled Estrogen Receptor 1 Mediates Acute Estrogen-Induced Cardioprotection via MEK/ERK/GSK-3β Pathway after Ischemia/Reperfusion.

Kabir, Mohammad E ; Singh, Harpreet ; Lu, Rong ; Olde, Björn LU ; Leeb-Lundberg, Fredrik LU and Bopassa, Jean Chrisostome (2015) In PLoS ONE 10(9).
Abstract
Three types of estrogen receptors (ER) exist in the heart, Esr1, Esr2 and the G protein-coupled estrogen receptor 1, Gper1. However, their relative importance in mediating estrogen protective action is unknown. We found that, in the male mouse ventricle, Gper1 transcripts are three- and seventeen-fold more abundant than Esr1 and Esr2 mRNAs, respectively. Analysis of the three ER knockouts (Esr1-/-, Esr2-/- and Gper1-/-) showed that only the Gper1-/- hearts lost their ability to be protected by 40 nM estrogen as measured by heart function, infarct size and mitochondrial Ca2+ overload, an index of mitochondrial permeability transition pore (mPTP) activity. Analysis of Akt, ERK1/2 and GSK-3β salvage kinases uncovered Akt and ERK1/2 transient... (More)
Three types of estrogen receptors (ER) exist in the heart, Esr1, Esr2 and the G protein-coupled estrogen receptor 1, Gper1. However, their relative importance in mediating estrogen protective action is unknown. We found that, in the male mouse ventricle, Gper1 transcripts are three- and seventeen-fold more abundant than Esr1 and Esr2 mRNAs, respectively. Analysis of the three ER knockouts (Esr1-/-, Esr2-/- and Gper1-/-) showed that only the Gper1-/- hearts lost their ability to be protected by 40 nM estrogen as measured by heart function, infarct size and mitochondrial Ca2+ overload, an index of mitochondrial permeability transition pore (mPTP) activity. Analysis of Akt, ERK1/2 and GSK-3β salvage kinases uncovered Akt and ERK1/2 transient activation by estrogen whose phosphorylation increased during the first 5 min of non-ischemic perfusion. All these increase in phosphorylation effects were abrogated in Gper1-/-. Inhibition of MEK1/2/ERK1/2 (1 μM U0126) and PI-3K/Akt (10 μM LY294002) signaling showed that the MEK1/2/ERK1/2 pathway via GSK-3β exclusively was responsible for cardioprotection as an addition of U0126 prevented estrogen-induced GSK-3β increased phosphorylation, resistance to mitochondrial Ca2+-overload, functional recovery and protection against infarction. Further, inhibiting PKC translocation (1 μM chelerythrin-chloride) abolished estrogen-induced cardioprotection. These data indicate that estrogen-Gper1 acute coupling plays a key role in cardioprotection against ischemia/reperfusion injury in male mouse via a cascade involving PKC translocation, ERK1/2/GSK-3β phosphorylation leading to the inhibition of the mPTP opening. (Less)
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; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
10
issue
9
article number
e0135988
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:26356837
  • wos:000360965800009
  • scopus:84944721260
  • pmid:26356837
ISSN
1932-6203
DOI
10.1371/journal.pone.0135988
language
English
LU publication?
yes
id
80c36145-19e5-4e2f-869e-b0b051376573 (old id 8042583)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26356837?dopt=Abstract
date added to LUP
2016-04-01 13:28:02
date last changed
2022-03-21 18:46:13
@article{80c36145-19e5-4e2f-869e-b0b051376573,
  abstract     = {{Three types of estrogen receptors (ER) exist in the heart, Esr1, Esr2 and the G protein-coupled estrogen receptor 1, Gper1. However, their relative importance in mediating estrogen protective action is unknown. We found that, in the male mouse ventricle, Gper1 transcripts are three- and seventeen-fold more abundant than Esr1 and Esr2 mRNAs, respectively. Analysis of the three ER knockouts (Esr1-/-, Esr2-/- and Gper1-/-) showed that only the Gper1-/- hearts lost their ability to be protected by 40 nM estrogen as measured by heart function, infarct size and mitochondrial Ca2+ overload, an index of mitochondrial permeability transition pore (mPTP) activity. Analysis of Akt, ERK1/2 and GSK-3β salvage kinases uncovered Akt and ERK1/2 transient activation by estrogen whose phosphorylation increased during the first 5 min of non-ischemic perfusion. All these increase in phosphorylation effects were abrogated in Gper1-/-. Inhibition of MEK1/2/ERK1/2 (1 μM U0126) and PI-3K/Akt (10 μM LY294002) signaling showed that the MEK1/2/ERK1/2 pathway via GSK-3β exclusively was responsible for cardioprotection as an addition of U0126 prevented estrogen-induced GSK-3β increased phosphorylation, resistance to mitochondrial Ca2+-overload, functional recovery and protection against infarction. Further, inhibiting PKC translocation (1 μM chelerythrin-chloride) abolished estrogen-induced cardioprotection. These data indicate that estrogen-Gper1 acute coupling plays a key role in cardioprotection against ischemia/reperfusion injury in male mouse via a cascade involving PKC translocation, ERK1/2/GSK-3β phosphorylation leading to the inhibition of the mPTP opening.}},
  author       = {{Kabir, Mohammad E and Singh, Harpreet and Lu, Rong and Olde, Björn and Leeb-Lundberg, Fredrik and Bopassa, Jean Chrisostome}},
  issn         = {{1932-6203}},
  language     = {{eng}},
  number       = {{9}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{G Protein-Coupled Estrogen Receptor 1 Mediates Acute Estrogen-Induced Cardioprotection via MEK/ERK/GSK-3β Pathway after Ischemia/Reperfusion.}},
  url          = {{http://dx.doi.org/10.1371/journal.pone.0135988}},
  doi          = {{10.1371/journal.pone.0135988}},
  volume       = {{10}},
  year         = {{2015}},
}