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Published on: June 11, 2020
Vagal nerve stimulation protects cardiac injury by attenuating mitochondrial dysfunction in a murine burn injury
Xiaojiong Lu1, Todd Costantini, Nicole E Lopez
1Division of Trauma, Surgical Critical Care and Burns, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA 92103, USA.
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 (pBad(136)) and Akt (pAkt(308)). 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.
Insights
Vagal nerve stimulation (VNS) protects heart tissue from burn injury by preventing mitochondrial dysfunction. This protective effect is mediated through M3-muscarinic acetylcholine receptors and PI3K/Akt signaling pathways.
Area of Science:
- Cardiovascular Research
- Mitochondrial Biology
- Trauma Medicine
Background:
- Burn injuries induce significant cardiac damage.
- Mitochondrial dysfunction is a key factor in burn-induced heart injury.
- Vagal nerve stimulation (VNS) is explored for its potential cardioprotective effects.
Purpose of the Study:
- To investigate the protective effects of VNS on cardiac injury following burn trauma.
- To elucidate the role of VNS in mitigating mitochondrial dysfunction in the heart post-burn.
- To identify the specific molecular pathways involved in VNS-mediated cardioprotection.
Main Methods:
- A murine model of burn injury was established.
- Mice were subjected to VNS post-burn, with or without M3-muscarinic acetylcholine receptor (M3-AchR) or PI3K inhibitor treatment.
- Cardiac tissue was analyzed for pathological changes, apoptosis, mitochondrial function, and key signaling pathway markers.
Main Results:
- Burn injury led to cardiac pathology, cardiomyocyte apoptosis, and mitochondrial dysfunction.
- VNS significantly attenuated these burn-induced cardiac injuries.
- VNS inhibited the release of pro-apoptotic factors by upregulating Bcl-2 and phosphorylating Bad and Akt, effects blocked by M3-AchR or PI3K inhibitors.
Conclusions:
- VNS confers significant protection against burn injury-induced cardiac damage.
- VNS-mediated cardioprotection is achieved by attenuating mitochondrial dysfunction.
- The M3-AchR and PI3K/Akt signaling pathways are crucial for the protective effects of VNS in cardiac injury.
