Empagliflozin-pretreated BMSC exosomes showed stronger protection against myocardial ischemia-reperfusion injury than untreated exosomes.
Evidence
This preclinical cell and mouse study tested exosomes from empagliflozin-pretreated bone marrow MSCs in neonatal cardiomyocyte hypoxia-reoxygenation and mouse MIRI models.
Caveat
The findings are limited to preclinical models with intramyocardial exosome delivery, so human efficacy and practical treatment delivery remain untested.
Simplified
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 and ameliorating cardiomyocyte injury.
CONCLUSION: Our findings demonstrated that EMPA enhanced exosome secretion from BMSCs. Both EMPA-EXO and EXO attenuated MIRI by upregulating ATAD3A, which promoted PINK1/PARKIN-dependent mitophagy. Notably, EMPA-EXO exhibitd superior therapeutic efficacy compared to EXO, suggesting a promising strategy for optimizing MSC-derived exosome therapy in ischemic heart disease.
Key numbers
9.7 × 10⁷ particles/mL
Increase in Exosome Yield
Exosome concentration from EMPA-pretreated .
< 0.001
Reduction in Myocardial Infarct Area
Comparison of infarct size between and in MIRI mice.
< 0.0001
Decrease in Apoptotic Cells
Assessment of in HL-1 cells after H/R injury.
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