Targeting cardiomyocyte-derived extracellular vesicle miR-574-5p protects against cognitive impairment induced by ischemia-reperfusion.

Abstract

BACKGROUND: Acute myocardial ischemia/reperfusion (MI/R) increases risk for cognitive decline, yet the underlying mechanisms mediating heart-brain communication remain poorly understood. Small extracellular vesicles (sEVs) have emerged as novel long-range signaling mediators and may play a critical role. METHODS: MI/R was induced by transient ligation of the left anterior descending artery. Cognitive performance was assessed using multiple behavioral tests. sEVs derived from cardiomyocytes were labeled to track their distribution and cellular uptake in the brain. Heart and brain tissues were analyzed for microRNAs (miRNAs) expression using bioinformatics, qPCR, and RNAScope. The role of specific miRNAs was investigated through genetic inhibition of cardiomyocyte-derived sEVs release using Rab27aMyh6-Cremice, pharmacological blockade of exosome, and AAV-mediated overexpression or knockdown. RESULTS: MI/R mice exhibited significant cognition deficits along with hypothalamic paraventricular nucleus (PVN) synaptic ultrastructural injury and dysfunction. sEVs released from injured cardiomyocytes were significantly elevated and preferentially accumulated in oxytocin neurons from the PVN. Inhibiting cardiomyocyte-derived sEVs ameliorated cognitive impairments and synaptic pathology. Conversely, injection of cardiomyocyte-derived sEVs into the PVN recapitulated MI/R-induced cognitive deficits. Among candidate miRNAs, miR-574-5p was identified as a key mediator. Its inhibition via miRNA sponge restored cognitive function. Bioinformatic analyses revealed that miR-574-5p targets genes involved in synaptic structure and GABAreceptor signaling. CONCLUSIONS: Cardiomyocyte-derived sEVs contribute to MI/R-induced cognitive impairment through miR-574-5p. Upon delivery to the PVN and uptake by oxytocin neurons, miR-574-5p suppresses synaptic and GABAreceptor-related proteins, leading to synaptic disruption and cognitive decline. Targeting this pathway may represent a promising therapeutic approach for cognitive dysfunction associated with heart disease.