Hypoxia-conditioned cardiomyocyte-derived exosomes attenuate myocardial injury via ANP-mediated M2 macrophage polarization.

Exosomes derived from various cells have been demonstrated to contribute to cardiac repair by regulating macrophage polarization in myocardial infarction. However, how exosomes secreted from cardiomyocytes under hypoxia-ischemia (Hypo-Exo) regulate macrophage polarization in the local tissues is elusive. This study aimed to determine the underlying mechanisms by which Hypo-Exo polarized M2 macrophages. Hypo-Exo was harvested from the supernatant of oxygen glucose deprivation (OGD)-conditioned H9c2, identified using transmission electron microscopy, nanoparticle tracking analysis, and western blot, and then applied to RAW264.7 and C57BL/6N mice. Echocardiography, TTC, H&E, Masson, and immunofluorescence staining were used to evaluate the therapeutic effects of Hypo-Exo in the MI mouse model. The effects of Hypo-Exo on RAW264.7 were examined by RT-qPCR. Hypo-Exo labeled with PKH26 could be engulfed by RAW264.7 cells and promote M2 macrophage polarization. Hypo-Exo inhibited atrial natriuretic peptide (ANP) mRNA expression in RAW264.7 cells, and three cargo miRNAs of Hypo-Exo were upregulated to degrade the ANP expression. Instead of downregulating ANP, OGD supernatant upregulated ANP expression to activate M1 macrophages. Our study demonstrated a novel mechanism that Hypo-Exo carried with miRNAs as a communicator to degrade the expression level of ANP mRNA in macrophages by which Hypo-Exo polarized M2 macrophages to improve recovery from MI in mice.