Vericiguat enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction through microRNA-1180-3p/ETS1 pathway

Abstract

Reversing cardiac fibrosis contributes to the restoration of cardiac function in acute myocardial infarction (MI). Exosomes-derived mesenchymal stem cells (MSCs) have been established as potential biomarkers of cardiovascular diseases. While vericiguat has demonstrated promising outcomes in MI via reverse hypertrophy and fibrosis, previous studies about vericiguat pretreatment with MSCs is limited. We aim at exploring whether exosomes derived from vericiguat pretreatment MSCs could augment cardioprotective function and the underlying mechanisms. In our study, exosomes isolated from MSCs (MSC-Exo) and pretreated with vericiguat (MSC^VER-Exo) were administered to cardiac fibroblasts (CFs) in vitro and male infarcted Sprague-Dawley rat hearts in vivo. In vivo, MSC^VER-Exo could significantly improve cardiac function and attenuate cardiac fibrosis and decrease the expression of α-smooth muscle actin (α-SMA), Ι and III collagen (Col Ι and Col III) compared to MSC-Exo treatment. In vitro, MSC^VER-Exo could also restrain proliferation, migration, and the profibrotic genes expression in CFs. miR-1180-3p was enrich in MSC^VER-Exo. Besides, miR-1180-3p could be delivered to CFs via Exo and alleviated TGF-β1-induced fibrosis through inhibiting ETS1 signaling. The elucidation of this mechanism suggested that exosomes derived from vericiguat pretreatment MSCs could improve cardioprotective effects through promoting CFs function. MiR-1180-3p targeting ETS1 played an important role in antifibrosis.