GATA-4 overexpressing BMSC-derived exosomes suppress H/R-induced cardiomyocyte ferroptosis.

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes overexpressing GATA-4 (Exos) can protect cardiac function. Mitochondrial permeability transition pore (mPTP) has a crucial role in ferroptosis. This study aimed to assess the mechanism of Exos in myocardial ischemia/reperfusion (I/R) injury. Exos were successfully excreted, and 185 differential expression miRNAs were obtained using bioinformatics. The Exos effectively suppressed hypoxia/reoxygenation (H/R)-induced cardiomyocytes' ferroptosis, while the effects were reversed by miR-330-3p inhibitor. miR-330-3p targeted negative regulated BAP1. The effects of miR-330-3p inhibitor were reversed by knock-down BAP1. Also, BAP1 reversed the effects of Exos on H/R-induced cardiomyocytes' ferroptosis by downregulating SLC7A11. Mechanistically, BAP1 interacted with IP3R and increased cardiomyocytes' Ca level, causing mPTP opening and mitochondrial dysfunction, promoting H/R-induced cardiomyocytes' ferroptosis. Moreover, hydrogen sulfide (HS) content was increased and regulated the keap1/Nrf2 signaling pathway by Exos treated. Exos effectively suppresses H/R-induced cardiomyocytes' ferroptosis by upregulating miR-330-3p, which regulates the BAP1/SLC7A11/IP3R axis and inhibits mPTP opening.