Dexmedetomidine prevents septic myocardial dysfunction in rats via activation of α7nAChR and PI3K/Akt- mediated autophagy

Biomed Pharmacother. 2019 Dec:120:109231. doi: 10.1016/j.biopha.2019.109231. Epub 2019 Sep 20.

Abstract

Background and purpose: Dexmedetomidine (Dex) has been shown to elicit cardio-protective effects in sepsis. The aim of this study was to investigate the role of autophagy in the protective effects of Dex and its possible mechanism in vivo and vitro.

Experimental approach: 6-8-week-old male Wistar rats were performed cecal ligation puncture (CLP) and administered 0.9% saline (CLP group), 50 μg/kg Dex (Dex group), Dex plus chloroquine (20 mg/kg; Dex + CQ group), or 40 μg/kg methyllycaconitin (Dex + MLA group), or 25 μM LY294002 (Dex + LY294002 group). After study, cardiac histology, cardiac function, level of autophagy, cardiomyocytes apoptosis and inflammatory mediators including protein IL-1β, IL-6, and TNF-α were measured. The LPS induced-H9C2 cardiomyocytes were treated with Dex, Dex + CQ and detected for cell apoptosis, autophagy level and cell cycle.

Key results: CLP-induced sepsis resulted in cardiac dysfunction, apoptosis, and inflammatory response. Dex exhibited protective effects on the myocardium by the induction of myocardial autophagy and ameliorated the LPS-induced blockade of autophagic flux in H9C2 cells. CQ was found to significantly inhibit Dex-mediated protection of myocardial apoptosis and inflammation. CLP rats treated with Dex in combination with MLA, an antagonist of α7 nicotinic acetylcholine receptor (α7nAChR), exhibited decreased autophagy and increased inflammation and cell death, identifying α7nAchR was involved in the Dex-mediated pathway. In addition, we found that the PI3K/Akt pathway is involved in Dex-mediated autophagy and convergent with α7nAChR-mediated stimulation of autophagy response.

Conclusions and implications: For the first time, these data indicate that autophagy is central in Dex-mediated cardio-protection in sepsis. These observations provide the foundation for further study, and may serve as the basis for innovative therapeutic strategies against septic myocardial dysfunction.

Keywords: Autophagy; Dexmedetomidine; Heart injury; Sepsis.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line
  • Cytokines / metabolism
  • Dexmedetomidine / pharmacology*
  • Disease Models, Animal
  • Heart Diseases / metabolism
  • Heart Diseases / microbiology
  • Heart Diseases / pathology
  • Heart Diseases / prevention & control*
  • Inflammation Mediators / metabolism
  • Male
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats, Wistar
  • Sepsis / complications
  • Sepsis / drug therapy*
  • Sepsis / microbiology
  • Signal Transduction
  • Ventricular Function, Left / drug effects
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*

Substances

  • Anti-Inflammatory Agents
  • Chrna7 protein, mouse
  • Cytokines
  • Inflammation Mediators
  • alpha7 Nicotinic Acetylcholine Receptor
  • Dexmedetomidine
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt