Adipose stem cells-derived microvesicles and chicken egg-derived exosomes attenuate cardiac ischemia/reperfusion injury through AKT/ERK/Nrf2/HO-1 axis to inhibit apoptosis and inflammation and restore autophagy

Aims: Myocardial ischemia/reperfusion (I/R) injury is an unsolved medical issue that is caused by additional injuries derived from reperfusion therapy for patients with acute myocardial infarction, one of the leading causes of morbidity and mortality in the world. Myocardial I/R injury causes unpredictable complications evoked by oxidative stress, endothelial dysfunction, dysregulated autophagy, apoptosis, and an imbalanced inflammatory response. Microvesicles (MVs) derived from adipose stem cells (ADSC) and egg-derived exosomes (EXOs) may confer antioxidant, anti-inflammatory, anti-apoptotic and tissue repair potential, showing potential in cardiovascular therapy. This study aims to investigate the therapeutic effects and mechanisms of MVs and EXOs on myocardial I/R injury. Methods and materials: To explore the underlying mechanisms, we examined the activation of the Akt and Erk signaling pathways, and analyzed the expression of endothelial nitric oxide synthase (eNOS), antioxidant proteins, autophagy, apoptotic related markers, and inflammatory cytokines. Key findings: Peri-cardiac ischemic treatment of MVs or EXOs improved I/R depressed eNOS-mediated microcirculation, inhibited ST segment elevation, restored the elevated left ventricular end-diastolic pressure toward normal level, improved systolic and diastolic dysfunction (±dp/dt), reduced infarct size, decreased troponin I and LDH level. Mechanistically, MVs or EXOs treatment activated the Akt/ERK/Nrf2/HO-1 pathway to inhibit several proinflammatory cytokines release, myocardial Bax/Bcl-2/Caspase-3 mediated apoptosis, and restored Beclin-1/LC3 II mediated autophagy following I/R injury. Histology also found MVs and EXOs treatment reduced cell disorganization, edema, leukocyte infiltration, and fibrosis. Significance: In conclusion, the application of ADSC-MVs and egg-EXOs mitigated myocardial I/R injury through Akt/ERK/Nrf2/HO-1 pathway to inhibit apoptosis and inflammation and restore autophagy.