Vagal nerve stimulation protects cardiac injury by attenuating mitochondrial dysfunction in a murine burn injury model

Authors

  • Xiaojiong Lu,

    1. Division of Trauma, Surgical Critical Care and Burns, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
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  • Todd Costantini,

    1. Division of Trauma, Surgical Critical Care and Burns, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
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  • Nicole E. Lopez,

    1. Division of Trauma, Surgical Critical Care and Burns, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
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  • Paul L. Wolf,

    1. Division of Trauma, Surgical Critical Care and Burns, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
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  • Ann-Marie Hageny,

    1. Division of Trauma, Surgical Critical Care and Burns, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
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  • James Putnam,

    1. Division of Trauma, Surgical Critical Care and Burns, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
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  • Brian Eliceiri,

    1. Division of Trauma, Surgical Critical Care and Burns, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
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  • Raul Coimbra

    Corresponding author
    • Division of Trauma, Surgical Critical Care and Burns, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
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Correspondence to: Raul COIMBRA, M.D., Ph.D., FACS, Division of Trauma, Surgical Critical Care, and Burns, Department of Surgery, University of California San Diego Health Sciences, 200 W. Arbor Drive #8896, San Diego, CA 92103, USA.

Tel.: (619)543 7100

Fax: (619)543 7202

E-mail: rcoimbra@ucsd.edu

Abstract

Mitochondria play a central role in the integration and execution of a wide variety of apoptotic signals. In the present study, we examined the deleterious effects of burn injury on heart tissue. We explored the effects of vagal nerve stimulation (VNS) on cardiac injury in a murine burn injury model, with a focus on the protective effect of VNS on mitochondrial dysfunction in heart tissue. Mice were subjected to a 30% total body surface area, full-thickness steam burn followed by right cervical VNS for 10 min. and compared to burn alone. A separate group of mice were treated with the M3-muscarinic acetylcholine receptor (M3-AchR) antagonist 4-DAMP or phosphatidylinositol 3 Kinase (PI3K) inhibitor LY294002 prior to burn and VNS. Heart tissue samples were collected at 6 and 24 hrs after injury to measure changes in apoptotic signalling pathways. Burn injury caused significant cardiac pathological changes, cardiomyocyte apoptosis, mitochondrial swelling and decrease in myocardial ATP content at 6 and 24 hrs after injury. These changes were significantly attenuated by VNS. VNS inhibited release of pro-apoptotic protein cytochrome C and apoptosis-inducing factor from mitochondria to cytosol by increasing the expression of Bcl-2, and the phosphorylation level of Bad (pBad136) and Akt (pAkt308). These protective changes were blocked by 4-DAMP or LY294002. We demonstrated that VNS protected against burn injury–induced cardiac injury by attenuating mitochondria dysfunction, likely through the M3-AchR and the PI3K/Akt signalling pathways.

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