Electroacupuncture Pretreatment Alleviates Myocardial Ischemia–Reperfusion Injury by Inhibiting Engulfment by Microglia in the Lateral Hypothalamus

ABSTRACT Aim The occurrence of myocardial ischemia–reperfusion injury (MIRI) is accompanied by neuroinflammatory reactions and is closely related to the overactivation of microglia. Currently, effective clinical strategies to prevent MIRI are unclear. This study investigated potential therapeutic targets and the mechanisms of electroacupuncture pretreatment (EA‐pre) for MIRI. Methods A MIRI mouse model was established by ligating the left anterior descending branch of the heart for 30 min and reperfusion for 2 h. The mechanisms by which EA‐pre alleviates MIRI were investigated through immunofluorescence staining, chemogenetics, and fiber photometry recordings, focusing on the potential involvement of microglia and glutamate (Glu) neurons in the lateral hypothalamic (LH). Results EA‐pre improves cardiac function in MIRI mice by suppressing microglial activation in the LH. The underlying mechanism likely involves EA‐pre inhibition of microglial engulfment of inhibitory synapses around LH Glu neurons. Targeted activation of LH microglia reverses EA's inhibitory effect, thereby increasing LH Glu neuronal activity and triggering overactivation of the sympathetic nervous system (SNS), which ultimately exacerbates MIRI. Conclusion EA‐pre inhibits microglial engulfment of inhibitory synapses around LH Glu neurons in MIRI mice, thereby suppressing LH Glu neuronal activity, reducing SNS output, and ultimately exerting cardioprotective effects.