Myocardial ischemia‐reperfusion injury (MIRI) is a major cause of heart failure in patients with coronary heart disease (CHD). Mitochondrial dysfunction is the crucial factor of MIRI; oxidative stress caused by mitochondrial reactive oxygen species (ROS) aggravates myocardial cell damage through the mitochondria‐dependent apoptosis pathway. Asiatic acid (AA) is a type of pentacyclic triterpene compound purified from the traditional Chinese medicine Centella asiatica, and its protective pharmacological activities have been reported in various disease models. This study is aimed at investigating the protective effects of AA and the underlying mechanisms in MIRI. To achieve this goal, an animal model of MIRI in vivo and a cell model of oxygen‐glucose deprivation/reperfusion (OGD/R) in vitro were established. The results show that AA exerts a protective effect on MIRI by improving cardiac function and reducing cardiomyocyte damage. Due to its antioxidant properties, AA alleviates mitochondrial oxidative stress, as evidenced by the stable mitochondrial structure, maintained mitochondrial membrane potential (MMP), and reduced ROS generation, otherwise due to its antiapoptotic properties. AA inhibits the mitogen‐activated protein kinase (MAPK)/mitochondria‐dependent apoptosis pathway, as evidenced by the limited phosphorylation of p38‐MAPK and JNK‐MAPK, balanced proportion of Bcl‐2/Bax, reduced cytochrome c release, inhibition of caspase cascade, and reduced apoptosis. In conclusion, our study confirms that AA exerts cardiac‐protective effects by regulating ROS‐induced oxidative stress via the MAPK/mitochondria‐dependent apoptosis pathway; the results provide new evidence that AA may represent a potential treatment for CHD patients.

A distinctive feature of ferroptosis is intracellular iron accumulation and the impairment of antioxidant capacity, resulting in a lethal accumulation of lipid peroxides leading to cell death. This study was conducted to determine whether inhibiting isocitrate dehydrogenase 1 (IDH1) may help to prevent foam cell formation by reducing oxidized low-density lipoprotein (ox-LDL)-induced ferroptosis in macrophages and activating nuclear factor erythroid 2-related factor 2 (NRF2). Gene expression profiling (GSE70126 and GSE70619) revealed 21 significantly different genes, and subsequent bioinformatics research revealed that ferroptosis and IDH1 play essential roles in foam cell production. We also confirmed that ox-LDL elevates macrophage ferroptosis and IDH1 protein levels considerably as compared with controls. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, reduced ox-LDL-induced elevated Fe²⁺ levels, lipid peroxidation (LPO) buildup, lactate dehydrogenase (LDH) buildup, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4), ferritin heavy polypeptide 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11) protein downregulation. More crucially, inhibiting IDH1 reduced Fe²⁺ overload, lipid peroxidation, LDH, and glutathione depletion, and elevated GPX4, FTH1, and SLC7A11 protein expression, resulting in a reduction in ox-LDL-induced macrophage ferroptosis. IDH1 inhibition suppressed ox-LDL-induced macrophage damage and apoptosis while raising NRF2 protein levels. We have demonstrated that inhibiting IDH1 reduces ox-LDL-induced ferroptosis and foam cell formation in macrophages, implying that IDH1 may be an important molecule regulating foam cell formation and may be a promising molecular target for the treatment of atherosclerosis.

Pigment epithelial-derived factor (PEDF) is known to exert diverse physiological activities. Previous studies suggest that hypoxia could induce mitophagy. Astoundingly, under hypoxic condition, we found that PEDF decreased the mitochondrial density of cardiomyocytes. In this study, we evaluated whether PEDF could decrease the mitochondrial density and play a protective role in hypoxic cardiomyocytes via promoting mitophagy. Immunostaining and western blotting were used to analyze mitochondrial density and mitophagy of hypoxic cardiomyocytes. Gas chromatography‑mass spectrometry and ELISA were used to analyze levels of palmitic acid and diacylglycerol. Transmission Electron Microscopy was used to detect mitophagy and the mitochondrial density in adult male Sprague-Dawley rat model of acute myocardial infarction. Compared to the control group, we observed that PEDF decreased mitochondrial density through promoting hypoxic cardiomyocyte mitophagy. PEDF increased the levels of palmitic acid and diacylglycerol, and then upregulated the levels of protein kinase Cα (PKC-α) and its activation. Furthermore, inhibition of PKC-α by Go6976 could effectively suppress PEDF-induced mitophagy. Besides, we found that PEDF promoted FUNDC1-mediated cardiomyocyte mitophagy via ULK1, which depended on the activation of PKC-α. Finally, we discovered that mitophagy was increased and mitochondrial density was reduced in adult male Sprague-Dawley rat model of acute myocardial infarction. We concluded that PEDF promotes mitophagy to protect hypoxic cardiomyocytes, through PEDF/PEDF-R/PA/DAG/PKC-α/ULK1/FUNDC1 pathway.

Objective: The aim of this study was to test the hypothesis whether serum level of calpains could become a meaningful biomarker for diagnosis of acute lung injury (ALI) in clinical after cardiac surgery using cardiopulmonary bypass (CPB) technology.Methods and results: Seventy consecutive adults underwent cardiac surgery with CPB were included in this prospective study. Based on the American-European Consensus Criteria (AECC), these patients were divided into ALI (n = 20, 28.57%) and non-ALI (n = 50, 71.43%) groups. Serum level of calpains in terms of calpains’ activity which was expressed as relative fluorescence unit (RFU) per microliter and measured at beginning of CPB (baseline), 1 h during CPB, end of CPB as well as 1, 12, and 24 h after CPB. Difference of serum level of calpains between two groups first appeared at the end of CPB and remained different at subsequent test points. Univariate and multivariate logistic regression analysis indicated that serum level of calpains 1 h after CPB was an independent predictor for postoperative ALI (OR 1.011, 95% CI 1.001, 1.021, p = 0.033) and correlated with a lower PaO₂/FiO₂ ratio in the first 2 days (The first day: r = -0.389, p < 0.001 and the second day: r = -0.320, p = 0.007) as well as longer mechanical ventilation time (r = 0.440, p < 0.001), intensive care unit (ICU) length of stay (LOS) (r = 0.419, p < 0.001) and hospital LOS (r = 0.297, p = 0.013).Conclusion: Elevated serum level of calpains correlate with impaired lung function and poor clinical outcomes, indicating serum level of calpains could act as a potential biomarker for postoperative ALI following CPB in adults.Clinical trial registration: [https://clinicaltrials.gov/show/NCT05610475], identifier [NCT05610475].

Acute lung injury (ALI) is a life-threatening complication of cardiac surgery that has a high rate of morbidity and mortality. Epithelial ferroptosis is believed to be involved in the pathogenesis of ALI. MOTS-c has been reported to play a role in regulating inflammation and sepsis-associated ALI. The purpose of this study is to observe the effect of MOTS-c on myocardial ischemia reperfusion (MIR)-induced ALI and ferroptosis. In humans, we used ELISA kits to investigate MOTS-c and malondialdehyde (MDA) levels in patients undergoing off-pump coronary artery bypass grafting (CABG). In vivo, we pretreated Sprague-Dawley rats with MOTS-c, Ferrostatin-1 and Fe-citrate(Ⅲ). We conducted Hematoxylin and Eosin (H&E) staining and detection of ferroptosis-related genes in MIR-induced ALI rats. In vitro, we evaluated the effect of MOTS-c on hypoxia regeneration (HR)-induced mouse lung epithelial-12 (MLE-12) ferroptosis and analyzed the expression of PPARγ through western blotting. We found that circulating MOTS-c levels were decreased in postoperative ALI patients after off-pump CABG, and that ferroptosis contributed to ALI induced by MIR in rats. MOTS-c suppressed ferroptosis and alleviated ALI induced by MIR, and the protective effect of MOTS-c- was dependent on PPARγ signaling pathway. Additionally, HR promoted ferroptosis in MLE-12 cells, and MOTS-c inhibited ferroptosis against HR through the PPARγ signaling pathway. These findings highlight the therapeutic potential of MOTS-c for improving postoperative ALI induced by cardiac surgery.