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

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.

Reduction of Mitochondria–Endoplasmic Reticulum Interactions by Acetylcholine Protects Human Umbilical Vein Endothelial Cells From Hypoxia/Reoxygenation Injury

“…Previous studies have demonstrated that acetylcholine and vagal nerve stimulation prevent cardiomyocyte apoptosis induced by multiple pathological insults, including ischemia or burn injury, likely through the PI3K/Akt pathway. 14,33 Consistent with those results, we found that the antiapoptotic effects of acetylcholine were reversed by the PI3K inhibitor LY294002. In addition, we found that acetylcholine treatment balanced the reduction of eNOS expression and phosphorylation after H/R and L-NAME abrogated the effects of acetylcholine, suggesting that acetylcholine likely acts, at least in part, by increasing eNOS levels.…”

Burn Serum Stimulates Myoblast Cell Death Associated with IL-6-Induced Mitochondrial Fragmentation

“…The morphologic change of mitochondrial swelling was reported in burn rats’ liver by electronic microscopic images (23), and also displayed indirectly in isolated fresh mitochondria from animal heart tissue at 6 and 24h (24). Swelling of mitochondrial cristae promotes ROS production and even leads to cell apoptosis (25).…”

Novel strategies and underlying protective mechanisms of modulation of vagal activity in cardiovascular diseases

“…Chronic vagal stimulation therapy significantly enhanced the expression of eNOS and suppressed that of iNOS and nNOS (Hamann et al ., ). eNOS activation by vagal stimulation may be associated with up‐regulation of the PI3K/Akt signalling cascade, mediated via muscarinic M 2 or M 3 receptors (Lu et al ., ; Miao et al ., ). These data are in agreement with the concept that PI3K/Akt is a critical upstream signalling component in the activation of eNOS (Morello et al ., ; He et al ., ).…”