Estrogen Alleviates Myocardial Ischemia-Reperfusion Injury by Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

BACKGROUND: The mechanism of estrogen-mediated myocardial protection remains incompletely understood. Our previous studies have shown that estrogen replacement therapy can modulate the expression of NLRP3 and alleviate inflammation in ovariectomized mice, while NLRP3 has been implicated in mediating cell pyroptosis. This study aimed to investigate the potential protective effects of 17β-estrogen (E2) on myocardial ischemia/reperfusion (I/R) injury by inhibiting NLRP3 inflammasome-mediated pyroptosis. METHODS AND RESULTS: Using an ovariectomy (OVX) mouse model of myocardial I/R, our findings revealed that E2 replacement therapy led to a significant reduction in infarct size and pyroptosis levels, accompanied by a decrease in the expressions of key pyroptosis-related proteins including TXNIP, NLRP3, cleaved Caspase-1, ASC, IL-1β, and GSDMD. In vitro experiments with H/R cardiomyocytes further supported these observations, as E2 treatment improved cell viability and reduced pyroptosis-related protein levels. Conversely, coadministration of the estrogen receptor antagonist ICI 182780 reversed the protective effects of E2. Additionally, treatment with the NLRP3 inhibitor Bay11-7082 and the Caspase-1 inhibitor AC-YVAD-CMK also attenuated pyroptosis. CONCLUSIONS: Collectively, these results suggest that estrogen may alleviate myocardial I/R injury by inhibiting pyroptosis through the ER/TXNIP/NLRP3/Caspase-1 pathway, offering insights into potential therapeutic strategies for cardiac ischemic injury.