Bone marrow mesenchymal stem cell (BMSC)-derived exosomes overexpressing GATA-4 (Exos(oe-GATA-4)) can protect cardiac function. Mitochondrial permeability transition pore (mPTP) has a crucial role in ferroptosis. This study aimed to assess the mechanism of Exos(oe-GATA-4) in myocardial ischemia/reperfusion (I/R) injury. Exos were successfully excreted, and 185 differential expression miRNAs were obtained using bioinformatics. The Exos(oe-GATA-4) 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(oe-GATA-4) on H/R-induced cardiomyocytes' ferroptosis by downregulating SLC7A11. Mechanistically, BAP1 interacted with IP3R and increased cardiomyocytes' Ca2+ level, causing mPTP opening and mitochondrial dysfunction, promoting H/R-induced cardiomyocytes' ferroptosis. Moreover, hydrogen sulfide (H2S) content was increased and regulated the keap1/Nrf2 signaling pathway by Exos(oe-GATA-4) treated. Exos(oe-GATA-4) effectively suppresses H/R-induced cardiomyocytes' ferroptosis by upregulating miR-330-3p, which regulates the BAP1/SLC7A11/IP3R axis and inhibits mPTP opening.
基金：
National Natural Science Foundation of China [82060299]; Medical Discipline Leader Project of Yunnan Provincial Health Commission [D-2019020]; Yunnan Provincial Government Ten Thousand Person-Top Young Talents Project [KH-SWR-QNBJ-2019-002]; Clinical Medical Center of the First People's Hospital of Yunnan Province [2021LCZXXF-XZ04, 2022LCZXKF-HX05]; Kunming Medical Joint Special Project-Outstanding Youth Cultivation Project [202101AY070001-034]; Kunming Medical joint special project [202101AY070001-272]; Famous Doctor Project of "Xingdian Talent Support Plan" of Yunnan Province [XDYC-MY-2022-0037]; Yunnan Province 2023 Undergraduate Education and Teaching Reform Research Project [2023BKXJJG-F04002]
