Aim This study aimed to investigate the correlation of lnc‐ANRIL/miR‐125a axis with risk, severity, inflammation, and prognosis of sepsis. Methods A hundred and twenty‐six sepsis patients and 125 healthy controls were recruited, and then, blood samples were collected, and plasma was separated for lnc‐ANRIL, miR‐125a, lnc‐ANRIL/miR‐125a axis, and inflammatory cytokine level detections. In addition, basic characteristics, 28‐day mortality, and accumulating survival of sepsis patients were recorded. Results Plasma lnc‐ANRIL expression was increased, miR‐125a expression was decreased, and lnc‐ANRIL/miR‐125a axis level was elevated in sepsis patients compared with healthy controls, and all of them had good value for predicting sepsis risk with AUCs of 0.800, 0.817, and 0.843, respectively. Lnc‐ANRIL and lnc‐ANRIL/miR‐125a axis were positively correlated with biochemical index levels including CRP and PCT levels, disease severity scale scores, and pro‐inflammatory cytokine levels in sepsis patients, while miR‐125a displayed the opposite trend. Lnc‐ANRIL and lnc‐ANRIL/miR‐125a axis expressions were elevated, while miR‐125a expression was declined in deaths compared with survivors, and all of them predicted 28‐day mortality in sepsis patients with AUCs of 0.765, 0.745, and 0.785, respectively. Subsequently, the Kaplan‐Meier analysis revealed that patients with high lnc‐ANRIL, low miR‐125a, and high lnc‐ANRIL/miR‐125a axis levels presented with worse accumulating survival. In addition, multivariate regression model analyses revealed that high plasma lnc‐ANRIL/miR‐125a axis was an independent predictive factor for both increased 28‐day mortality and worse accumulating survival. Conclusion Circulating lnc‐ANRIL/miR‐125a axis was upregulated and could serve as a biomarker for severity, inflammation, and prognosis in sepsis patients.
A previous study found that transmembrane protein 43 (TMEM43) was highly associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy. However, as a transmembrane protein, TMEM43 may be involved in ferroptosis in cardiovascular disease. In this study, we aimed to explore the role of TMEM43 in lipopolysaccharide (LPS)-induced cardiac injury and the underlying mechanism. Mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis. Mice were also subjected to AAV9-shTMEM43 to knock down TMEM43 or AAV9-TMEM43 to overexpress TMEM43 in hearts. H9c2 rat cardiomyocytes were also transfected with Ad-TMEM43 or TMEM43 siRNA to overexpress/knock down TMEM43. As a result, TMEM43 knockdown in hearts deteriorated LPS-induced mouse cardiac injury and dysfunction. LPS increased cardiac ferroptosis as assessed by malonaldehyde (MDA) and cardiac iron density, which were aggravated by TMEM43 knockdown. Moreover, TMEM43 overexpression alleviated LPS-induced cardiac injury, dysfunction, and ferroptosis. In vitro experiments showed that TMEM43 overexpression inhibited LPS-induced lipid peroxidation and cardiomyocyte injury while TMEM43 knockdown aggravated LPS-induced ferroptosis and injury in cardiomyocytes. Mechanistically, LPS increased the expression of P53 and ferritin but decreased the level of Gpx4 and SLC7A11. TMEM43 could inhibit the level of P53 and ferritin enhanced the level of Gpx4 and SLC7A11. Furthermore, ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, could protect against LPS-induced cardiac injury and also counteracted the deteriorating effects of TMEM43 silencing in the heart. Based on these findings, we concluded that TMEM43 protects against sepsis-induced cardiac injury via inhibiting ferroptosis in mice. By targeting ferroptosis in cardiomyocytes, TMEM43 may be a therapeutic strategy for preventing sepsis in the future.
Klotho is a novel anti-aging hormone involved in human coronary artery disease. The present study aimed to detect the effects and mechanism of Klotho on cardiomyocytes in a hypoxia/reoxygenation (H/R) model in vitro. Neonatal Sprague-Dawley rat cardiomyocytes were randomly distributed into experimental groups as follows: Control group; H/R group, 4‑h hypoxia followed by 3‑h reoxygenation; and H/R+Klotho group, incubated with 0.1, 0.2 or 0.4 µg/ml Klotho protein for 16 h and then subjected to 4‑h hypoxia/3‑h reoxygenation. In order to evaluate cardiomyocyte damage, cell viability and lactate dehydrogenase (LDH) levels were measured. Cell apoptosis was measured by flow cytometry. The 2',7'-dichlorofluorescein diacetate reagent was used to estimate the intracellular generation of reactive oxygen species (ROS). Immunofluorescence staining was used to test whether Klotho induced decreased nuclear translocation of forkhead box protein O1 (FOXO1). Western blot analysis was performed to detect protein levels of FOXO1, phospho-FOXO1, Akt, phospho-Akt and superoxide dismutase 2 (SOD2). Cell viability was significantly decreased, levels of LDH in the cardiomyocyte culture medium were significantly increased and the apoptotic rate was enhanced in the H/R group when compared with those of the control group. Compared with the H/R group, cell viability of the H/R+Klotho groups was significantly higher (P<0.05). Treatment with Klotho protein resulted in a significant resistance of cardiomyocytes to apoptosis and the release of LDH was decreased. Intracellular ROS levels in the H/R group were significantly elevated above those of the control group (P<0.05). Following treatment with Klotho, intracellular ROS levels were significantly decreased compared with those of the H/R group (P<0.05). Western blot analysis confirmed that Klotho protein treatment increased FOXO1 levels in the nucleus and decreased FOXO1 levels in the cytoplasm. Furthermore, exogenous Klotho protein promoted translocation of FOXO1 from cytoplasm to nucleus. In addition, the administration of Klotho protein suppressed phosphorylation of FOXO1 and Akt, and markedly increased the protein expression levels of SOD2. In conclusion, treatment with Klotho protein had beneficial effects on cardiomyocytes undergoing H/R injury. The mechanism of this effect may be associated with suppressed apoptosis of cardiomyocytes, inhibition of phosphorylation of FOXO1 and Akt as well as suppression of cytoplasm transfer of FOXO1.
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