Empagliflozin-pretreated BMSC exosomes attenuate myocardial ischemia-reperfusion injury by enhancing atad3a/pink1-dependent mitophagy
Abstract
BACKGROUND AND OBJECTIVES: Mounting evidence demonstrates that exosomes derived from mesenchymal stem cells (MSCs) can mitigate myocardial ischemia-reperfusion injury (MIRI). However, the therapeutic potential of untreated MSC-derived exosomes remains limited. Here, we investigate whether exosomes derived from sodium-glucose co-transporter 2 inhibitor (SGLT2i)-pretreated MSCs exhibit enhanced cardioprotective effects against MIRI and elucidate the underlying mechanisms.
METHODS AND RESULTS: Mouse bone marrow-derived MSCs (BMSCs) were pretreated with the SGLT2 inhibitor empagliflozin (EMPA), and the secreted exosomes (EMPA-EXO) were isolated. Primary neonatal cardiomyocytes were co-cultured with EMPA-EXO or untreated exosomes (EXO) for 24 h before hypoxia-reoxygenation (H/R) injury. In the MIRI mice, EXO or EMPA-EXO were delivered via intramyocardial injection. EMPA pretreatment significantly augmented exosome secretion from BMSCs by modulating the expression of Alix, nsmase2, and RAB27a. In vitro, both EXO and EMPA-EXO enhanced cardiomyocyte viability, attenuated cellular damage, and suppressed apoptosis following H/R injury. In vivo, EMPA-EXO and EXO administration improved cardiac function, reduced myocardial apoptosis, and diminished infarct size in MIRI mice mice. Mechanistically, Western blot and transmission electron microscopy (TEM) revealed that both exosome types upregulated ATAD3A expression, thereby activating PINK1/PARKIN-mediated mitophagy and ameliorating…
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