Myocardial dysfunction is an important manifestation of sepsis. Previous studies suggest that melatonin is protective against sepsis. In addition, activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway has been reported to be beneficial in sepsis. However, the role of PI3K/Akt signaling in the protective effect of melatonin against sepsis-induced myocardial dysfunction remains unclear. Here, LY294002, a PI3K inhibitor, was used to investigate the role of PI3K/Akt signaling in mediating the effects of melatonin on sepsis-induced myocardial injury. Cecal ligation and puncture (CLP) surgery was used to establish a rat model of sepsis. Melatonin was administrated to rats intraperitoneally (30 mg/kg). The survival rate, measures of myocardial injury and cardiac performance, serum lactate dehydrogenase level, inflammatory cytokine levels, oxidative stress level, and the extent of myocardial apoptosis were assessed. The results suggest that melatonin administration after CLP surgery improved survival rates and cardiac function, attenuated myocardial injury and apoptosis, and decreased the serum lactate dehydrogenase level. Melatonin decreased the production of the inflammatory cytokines TNF-α, IL-1β, and HMGB1, increased anti-oxidant enzyme activity, and decreased the expression of markers of oxidative damage. Levels of phosphorylated Akt (p-Akt), unphosphorylated Akt (Akt), Bcl-2, and Bax were measured by Western blot. Melatonin increased p-Akt levels, which suggests Akt pathway activation. Melatonin induced higher Bcl-2 expression and lower Bax expression, suggesting inhibition of apoptosis. All protective effects of melatonin were abolished by LY294002, the PI3K inhibitor. In conclusion, our results demonstrate that melatonin mitigates myocardial injury in sepsis via PI3K/Akt signaling activation.
Myocardial dysfunction is a major manifestation of sepsis and closely associated with the increased mortality. MicroRNA-146 is one of the most important microRNAs identified as a potent negative regulator in innate immune and inflammatory responses induced by lipopolysaccharide (LPS). We aimed to identify the role and potential regulatory mechanism of miR-146a in sepsis-induced cardiac dysfunction with the induction of ErbB4 signaling. H9C2 cells were treated with LPS to induce sepsis, and miR-146a overexpression significantly increased the cell viability, reduced the apoptosis and ROS level, and attenuated the release of proinflammatory cytokines including TNF-α and IL-1β. Levels of ErbB4, p-NF-κB, NF-κB, TRAF6, IRAK1, caspase 3, Bcl-2, and Bax were measured by Western blot. The overexpression of miR-146a significantly increased the ErbB4 expression, decreased the expression of TRAF6, IRAK1, caspase 3, and the phosphorylation level of NF-κB, and also increased the Bcl-2/Bax ratio, suggesting the inhibition of inflammation and apoptosis. The protective effects were all abolished by the use of siErbB4. In conclusion, our results demonstrated that the overexpression of miR-146a mitigates myocardial injury by negatively regulating NF-κB activation and inflammatory cytokine production via targeting ErbB4 in LPS-induced sepsis.
Aim: Betulin is a pentacyclic triterpenoid isolated from the bark of yellow and white birch trees with anti-cancer and anti-malaria activities. In this study we examined the effects of betulin on atherosclerosis in apoE -/-mice and the underlying mechanisms. Methods: Murine macrophage RAW264.7 cells and human monocyte-derived THP-1 cells were tested. Foam cell formation was detected with Oil Red O staining. Cholesterol efflux was assessed using [3 H]-cholesterol efflux assay. The expression of ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) was examined using RT-PCR and Western-blotting. The ABCA1 promoter activity was evaluated using luciferase activity assay. Male apoE -/-mice fed on a high-fat-diet (HFD), and received betulin (20 and 40 mg·kg -1 ·d -1, ig) for 12 weeks. The macrophage content and ABCA1 expression in the aortic sinuses were evaluated with immunofluorescence staining. The hepatic, intestinal and fecal cholesterol were also analyzed in the mice. Results: In RAW264.7 cells, betulin (0.1-2.5 μg/mL) dose-dependently ameliorated oxLDL-induced cholesterol accumulation and enhanced cholesterol efflux. In both RAW264.7 and THP-1 cells, betulin increased the expression of ABCA1 and ABCG1 via suppressing the transcriptional repressors sterol-responsive element-binding proteins (SREBPs) that bound to E-box motifs in ABCA1 promoter, whereas E-box binding site mutation markedly attenuated betulin-induced ABCA1 promoter activity. In HFD-fed apoE -/-mice, betulin administration significantly reduced lesions in en face aortas and aortic sinuses. Furthermore, betulin administration significantly increased ABCA1 expression and suppressed macrophage positive areas in the aortic sinuses. Moreover, betulin administration improved plasma lipid profiles and enhanced fecal cholesterol excretion in the mice. Conclusion: Betulin attenuates atherosclerosis in apoE -/-mice by promoting cholesterol efflux in macrophages.
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