| First Author | Kabir ME | Year | 2015 |
| Journal | PLoS One | Volume | 10 |
| Issue | 9 | Pages | e0135988 |
| PubMed ID | 26356837 | Mgi Jnum | J:243105 |
| Mgi Id | MGI:5907597 | Doi | 10.1371/journal.pone.0135988 |
| Citation | Kabir ME, et al. (2015) G Protein-Coupled Estrogen Receptor 1 Mediates Acute Estrogen-Induced Cardioprotection via MEK/ERK/GSK-3beta Pathway after Ischemia/Reperfusion. PLoS One 10(9):e0135988 |
| abstractText | 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-3beta 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 muM U0126) and PI-3K/Akt (10 muM LY294002) signaling showed that the MEK1/2/ERK1/2 pathway via GSK-3beta exclusively was responsible for cardioprotection as an addition of U0126 prevented estrogen-induced GSK-3beta increased phosphorylation, resistance to mitochondrial Ca2+-overload, functional recovery and protection against infarction. Further, inhibiting PKC translocation (1 muM 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-3beta phosphorylation leading to the inhibition of the mPTP opening. |
