Remote electroacupuncture conditioning protects the heart via fine-tuning the dual role of the SDF-1α/CXCR4 axis in myocardial ischemia–reperfusion injury

BACKGROUND: Remote electroacupuncture (EA) conditioning on forearm protects against myocardial ischemia-reperfusion injury (MIRI). However, the cardioprotective mechanisms of RIC have not been fully elucidated. This study aimed to investigate whether EA could balance the pro-survival and pro-inflammatory responses in MIRI rats via SDF-1α/CXCR4 axis. METHODS: SD rats were subjected to MIRI and underwent EA treatment before reperfusion therapy. Infarct size, cardiac function, and neutrophil infiltration were evaluated after 24-h of reperfusion. The mRNA and protein levels of SDF-1α in the myocardial border and infarct zones, were measured by RT-qPCR and Western blotting to reveal its spatial distribution. We examined serum SDF-1α levels and its myocardial scavenger receptor CXCR7 expression to elucidate the mechanism underlying its spatial distribution. Then, CXCR4/ERK pathway was evaluated at 15 min and 24 h after EA to examine the time-dependent dual effects of SDF-1α on CXCR4. RESULTS: Our results showed that EA attenuated infarct size and mortality, improved cardiac function after 24 h of MIRI. We identify that SDF-1α is a key humoral factor mediating EA-induced cardioprotection. In ischemic myocardium, the infarct zone exhibited a higher SDF-1α concentration than the border zone following EA treatment, a difference potentially linked to the elevated expression of CXCR7 in the border zone. In the early phase of reperfusion (15 min), our study showed that EA promoted the expression of the CXCR4 receptor, which in turn triggered ERK activation. This rapid ERK activation via SDF-1α/CXCR4 promoted cardiomyocyte survival and attenuated reperfusion-induced apoptosis. While at 24 h post-reperfusion, saturating signals of SDF-1α by EA downregulated CXCR4 expression, along with phosphorylation of its downstream effectors ERK and NF-κB p65. This coordinated downregulation facilitates inflammatory resolution by promoting neutrophil apoptosis. CONCLUSIONS: Cardioprotection by EA can be mediated by humoral factors SDF-1α that accumulate in infarct myocardium. SDF-1α triggers pro-survival CXCR4/ERK signaling at 15 min of reperfusion, whereas it promotes neutrophil apoptosis via CXCR4 degradation to facilitate inflammatory resolution by 24 h, thereby fine-tuning the dual role of the SDF-1α/CXCR4 axis in MIRI.