An acute estrogen receptor agonist enhances protective effects of cardioplegia in hearts from aging male and female mice

BACKGROUND: The G-protein coupled estrogen receptor (GPER) mediates rapid responses to estrogen. GPER activation may contribute to cardioprotective effects of estrogen in ischemia and reperfusion, although whether it is beneficial in aging myocardium is unclear. We determined whether a GPER agonist (G1) added to standard cardioplegic solution (used to protect hearts from ischemia-reperfusion injury during cardiac surgery) would improve outcomes in isolated hearts from adult and aged mice of both sexes. METHODS: Hearts from young adult (6-9 mos) and older (22-28 mos) mice were perfused with Krebs-Henseleit buffer for 15 min (37 °C) followed by cold (6-7 °C) St. Thomas'2 cardioplegia with G1 (0.5 μM), G1 (0.5 μM) plus G15 (GPER antagonist; 1 μM) or vehicle for 6 min. Hearts were then subjected to global ischemia (90 min; 23-24 °C) and reperfusion (30 min; 37 °C). Infarct size was quantified with triphenyltetrazolium chloride. RESULTS: In adult females, left ventricular developed pressure (LVDP) recovered to only 45.1 ± 11.9% of baseline in control hearts in reperfusion, but recovered to 76.5 ± 3.9% with G1 treatment (p < 0.05) and this was blocked by G15. Similar results were obtained in older males and females (LVDP = 51.5 ± 10.6% vs. 84.8 ± 8.7% and 51.9 ± 5.5% vs. 90.0 ± 6.1% for older males and females, respectively; p < 0.05). By contrast, G1 had no effect on recovery of LVDP in hearts from adult males (26.6 ± 8.9% vs. 46.0 ± 14.2%). The rates of pressure development and decay showed a similar pattern of recovery in reperfusion. Infarcts were significantly smaller in G1-treated hearts from all older mice and in younger females, although G1 had no impact on infarct size in adult males (48.1 ± 7.7% for control vs. 32.6 ± 8.0% for G1). CONCLUSION: G1 enhances cardioprotective properties of a standard cardioplegic solution in the aging myocardium of both sexes. Supplementation of cardioplegic solutions with GPER agonists is a potential translational intervention that may improve cardiac surgery outcomes in older adults.