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Background and Aims The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. Methods The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. Results Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase–DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. Conclusions ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation. [ABSTRACT FROM AUTHOR]

• The hydrogel Pluronic F127 is compatible with mitochondria and forms a stable three-dimensional structure. • PF127 hydrogel could enhance the survival of the translated mitochondria in the transplantation environment. • PF127-assisted mitochondria improved the energy metabolism of cardiomyocytes and provide better protection for myocardial I/R injury. Mitochondria play a central role in myocardial ischemia-reperfusion (I/R) injury. Therefore, mitochondrial transplantation (MTP) holds therapeutic potential for treating I/R injury. However, the transplantation environment (TE) could cause mitochondrial damage due to its high calcium concentration and physiological temperature, thus reducing MTP efficiency. Here, we use the hydrogel Pluronic F127 (PF127) to protect mitochondria during MTP to treat myocardial I/R injury. Our findings demonstrate that PF127 is compatible with mitochondria and forms a stable three-dimensional structure to encapsulate and protect them from the TE. PF127 significantly improves mitochondrial membrane potential (Δψm) and structural integrity. Additionally, PF127 enhances the internalization of transplanted mitochondria into cardiomyocytes. Our in vivo findings reveal that transplantation with PF127-encapsulated mitochondria improves cardiac function, reduces infarction size, and ameliorates adverse myocardial remodeling in mice after I/R injury. Likewise, our in vitro results indicate that this PF127-assisted MTP significantly improved the mechanic and metabolic capacities of cardiomyocytes after hypoxia-reoxygenation injury. These cardioprotective effects have been found to occur via the inhibition of apoptosis and oxidative stress. In conclusion, PF127 attenuates TE-induced mitochondrial dysfunction and enhances the therapeutic effects of MTP on myocardial I/R injury. [ABSTRACT FROM AUTHOR]

[Display omitted] Myocardial Ischemia/Reperfusion (MI/R) injury, a globally leading cause of mortality and disability, is commonly characterized by myriad inflammatory microenvironments, e.g. high level of reactive oxygen species (ROS), which has a high association with the consequent cell apoptosis and myocardial fibrosis. Herein, a reshaping strategy of cardiac microenvironments has been developed for relieving MI/R injury based on a biomimetic nanosystem (Pd@CeO 2 -M), which is composed of exterior macrophage-derived extracellular vesicles (MEVs) and encapsulated Pd@CeO 2 heterostructures. Due to rapid electrons transfer on the interface, the Pd@CeO 2 heterostructures exhibited outstanding ROS scavenging ability. The expression of Mac-1 and CD44 on the surface of Pd@CeO 2 -M contributes to adsorbing to the inflamed endothelium and efficient cellular uptake within damaged cardiac microenvironments, thus allowing for inflammation-targeting ability. In the mouse model of MI/R injury, Pd@CeO 2 -M accumulated and remained in the heart region over 24 hours. More importantly, Pd@CeO 2 -M regulated immune response and promoted anti-apoptotic and anti-inflammatory processes via upregulating the PI3K/Akt signaling pathway and inhibiting the TLR4/p38MAPK and TLR4/NF-κB signaling pathways, dissipated interstitial edema, triggered prominent angiogenesis, and ultimately improved cardiac function and ventricular remodeling. Overall, the Pd@CeO 2 -M heterostructures will provide an ideal paradigm of biomimetic nanomedicine confronting inflammatory diseases. [ABSTRACT FROM AUTHOR]

Autophagy is critically involved in myocardial ischemia-reperfusion (I/R). Autophagy inhibition exacerbates myocardial I/R injury. Few effective agents target autophagy to prevent myocardial I/R injury. Effective drugs that promote autophagy in myocardial I/R warrant further investigation. Galangin (Gal) enhances autophagy and alleviates I/R injury. Here we conducted both in vivo and in vitro experiments to observe the changes in autophagy after galangin treatment and investigated the cardioprotective effects of galangin on myocardial I/R. After 45-min occlusion of the left anterior descending coronary artery, myocardial I/R was induced by slipknot release. One day before surgery and immediately after surgery, the mice were injected intraperitoneally with the same volume of saline or Gal. The effects of Gal were evaluated using echocardiography, 2,3,5-triphenyltetrazolium chloride staining (TTC staining), western blotting, and transmission electron microscopy. Primary cardiomyocytes and bone marrow–derived macrophages were extracted in vitro to measure the cardioprotective effects of Gal. Compared with the saline-treated group, Gal significantly improved cardiac function and limited infarct enlargement after myocardial I/R. In vivo and in vitro studies demonstrated that Gal treatment promoted autophagy during myocardial I/R. The anti-inflammatory effects of Gal were validated in bone marrow–derived macrophages. These results strongly suggest that Gal treatment can attenuate myocardial I/R injury. Our data demonstrated that Gal could improve left ventricular ejection fraction and reduce infarct size after myocardial I/R by promoting autophagy and inhibiting inflammation. [ABSTRACT FROM AUTHOR]