Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism

Abstract

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.

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Acknowledgments

This study was supported by Grants from the National Natural Science Foundation of China (81170185).

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Correspondence to Lijun Sun.

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R. An and L. Zhao contributed equally to this work.

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An, R., Zhao, L., Xi, C. et al. Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism. Basic Res Cardiol 111, 8 (2016). https://doi.org/10.1007/s00395-015-0526-1

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Keywords

  • Sepsis
  • Myocardial dysfunction
  • Melatonin
  • Cecal ligation and puncture
  • Inflammation
  • Oxidative stress
  • PI3K/Akt signaling