title: 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.
authors.affiliation: Department of Radiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: An
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Baoji City People's Hospital, Baoji, 721000, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Xi
authors.affiliation: Department of Radiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Haixun
authors.initials: H
authors.lastname: Li
authors.affiliation: Integrated Branch, Armed Police Corps Hospital of Shanxi Province, Taiyuan, 030006, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Shen
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Haixiao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Physiology, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Shumiao
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China. sunljfmmu@163.com.
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D008550:Melatonin
keywords: Cecal ligation and puncture; Inflammation; Melatonin; Myocardial dysfunction; Oxidative stress; PI3K/Akt signaling; Sepsis