Affiliation:
1. Division of Molecular Medicine, Department of Anesthesiology,
2. Department of Molecular and Medical Pharmacology, and
3. Brain Research Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California
4. Department of Physiology and
Abstract
Several studies have recently demonstrated that G protein-coupled receptor 30 (GPER) can directly bind to estrogen and mediate its action. We investigated the role and the mechanism of estrogen-induced cardioprotection after ischemia-reperfusion using a specific GPER agonist G1. Isolated hearts from male mice were perfused using Langendorff technique with oxygenated (95% O2 and 5% CO2) Krebs Henseleit buffer (control), with G1 (1 μM), and G1 (1 μM) together with extracellular signal-regulated kinase (Erk) inhibitor PD-98059 (5μM). After 20 min of perfusion, hearts were subjected to 20 min global normothermic (37°C) ischemia followed by 40 min reperfusion. Cardiac function was measured, and myocardial necrosis was evaluated by triphenyltetrazolium chloride staining at the end of the reperfusion. Mitochondria were isolated after 10 min of reperfusion to assess the Ca2+ load required to induce mitochondria permeability transition pore (mPTP) opening. G1-treated hearts developed better functional recovery with higher rate pressure product (RPP, 6140 ± 264 vs. 2,640 ± 334 beats·mmHg−1·min−1, P < 0.05). The infarct size decreased significantly in G1-treated hearts (21 ± 2 vs. 46 ± 3%, P < 0.001), and the Ca2+ load required to induce mPTP opening increased (2.4 ± 0.06 vs. 1.6 ± 0.11 μM/mg mitochondrial protein, P < 0.05) compared with the controls. The protective effect of G1 was abolished in the presence of PD-98059 [RPP: 4,120 ± 46 beats·mmHg−1·min−1, infarct size: 53 ± 2%, and Ca2+ retention capacity: 1.4 ± 0.11 μM/mg mitochondrial protein ( P < 0.05)]. These results suggest that GPER activation provides a cardioprotective effect after ischemia-reperfusion by inhibiting the mPTP opening, and this effect is mediated by the Erk pathway.
Publisher
American Physiological Society
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
155 articles.
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