Article

Reactive Oxygen Species and Mitochondrial Adenosine Triphosphate-Regulated Potassium Channels Mediate Helium-Induced Preconditioning Against Myocardial Infarction In Vivo

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Journal of cardiothoracic and vascular anesthesia (Impact Factor: 1.48). 09/2008; 22(4):554-9. DOI: 10.1053/j.jvca.2008.04.005
Source: PubMed

ABSTRACT Helium produces preconditioning by activating prosurvival kinases, but the roles of reactive oxygen species (ROS) or mitochondrial adenosine triphosphate-regulated potassium (K(ATP)) channels in this process are unknown. The authors tested the hypothesis that ROS and mitochondrial K(ATP) channels mediate helium-induced preconditioning in vivo.
A randomized, prospective study.
A university research laboratory.
Male New Zealand white rabbits.
Rabbits (n = 64) were instrumented for the measurement of systemic hemodynamics and subjected to a 30-minute left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. In separate experimental groups, rabbits (n = 7 or 8 per group) were randomly assigned to receive 0.9% saline (control) or 3 cycles of 70% helium-30% oxygen administered for 5 minutes interspersed with 5 minutes of an air-oxygen mixture before LAD occlusion with or without the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2 mercaptoproprionyl glycine (2-MPG; 75 mg/kg), or the mitochondrial K(ATP) antagonist 5-hydroxydecanoate (5-HD; 5 mg/kg). Statistical analysis of data was performed with analysis of variance for repeated measures followed by Bonferroni's modification of a Student t test.
The myocardial infarct size was determined by using triphenyltetrazolium chloride staining and presented as a percentage of the left ventricular area at risk. Helium significantly (p < 0.05) reduced infarct size (23 +/- 4% of the area at risk; mean +/- standard deviation) compared with control (46 +/- 3%). NAC, 2-MPG, and 5-HD did not affect irreversible ischemic injury when administered alone (49 +/- 5%, 45 +/- 6%, and 45 +/- 3%), but these drugs blocked reductions in infarct size produced by helium (45 +/- 4%, 45 +/- 2%, and 44 +/- 3%).
The results suggest that ROS and mitochondrial K(ATP) channels mediate helium-induced preconditioning in vivo.

Download full-text

Full-text

Available from: Dorothee Weihrauch, Aug 20, 2015
0 Followers
 · 
100 Views
  • Source
    • "Helium is safe for use in clinical practice and diving because of its favourable characteristics and the lack of hemodynamic side effects. Recent experimental research has convincingly shown the protective properties of helium against ischemia in the heart [4] [5] [6] [7] [8] [9] [10] and the brain [11] [12] [13]. These organs can be protected against I/R injury by subjecting them to several short helium episodes according to a specific protocol, known as helium preconditioning (HPC) [4–10,13]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background & Aims: Hepatic ischemia and reperfusion (I/R) injury is a major complication of liver transplantation, hepatic resection and trauma. Helium preconditioning (HPC) exerts protection against ischemic stress. We investigated potential beneficial effects of HPC on I/R-induced liver injury and investigated mechanisms underlying HPC-induced protection. Methods: We employed a model of segmental warm hepatic I/R on BALB/c mice. Serum ALT was measured and livers were analysed by histology, RT-PCR and western blot. HPC was induced by inhalation of a 70% helium/30% oxygen mixture for three 5-min periods, interspersed with three 5-min washout periods by room air. We tested which component of HPC (the helium/air mixture inhalation, the air room gap, or the interaction between these two factors) is protective. Results: We found that HPC caused a significant increase in Akt phosphorylation in hepatocytes. The HPC-induced Akt phosphorylation resulted in decreased hepatocellular injury and improved survival rate of the treated animals. PI3K inhibitors abolished HPC induced effects. HPC-induced Akt phosphorylation affected expression of its downstream molecules. The effects of HPC on the PI3K/Akt pathway were attenuated by adenosine A(2A) receptor blockade, but could be re-established by PTEN inhibition. We demonstrated that the interaction of helium/air breathing and air gaps is responsible for the observed effects of HPC. Conclusions: HPC may be a promising strategy leading to a decrease in I/R induced liver injury in clinical settings. Additionally, the PI3K/Akt pathway plays an essential role in the protective effects of HPC in hepatic I/R injury.
    Journal of Hepatology 06/2014; 61(5). DOI:10.1016/j.jhep.2014.06.020 · 10.40 Impact Factor
  • Source
    • "They suggested helium induced cardioprotection by (1) the activation of pro-survival signaling kinases [18]; (2) the inhibition of the formation of mitochondrial permeability transition pores [21]; and (3) maintaining intracellular acidosis [22]. They found that reactive oxygen species and mitochondrial K ATP channels [19], nitric oxide [20], and opioid receptors [23] are all responsible for mediating helium induced cardioprotection for ischemic injury. It is very likely that multiple mechanisms and mediators may be involved in ischemic injury protection for heliox therapy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Manipulation of inhaled gases during ischemia/reperfusion is a potential novel therapy for acute stroke. We previously found that treatment with a mixture of 70%/30% helium/oxygen (heliox) or 100% oxygen protects the brain against acute focal ischemia-reperfusion injury. This study evaluates the potential neuro-protective effects of delayed heliox treatment and its dose response effects in a rat transient focal cerebral ischemia model. Adult male rats were subjected to 2-h middle cerebral artery occlusion and then assigned to 1 of 4 inhaled gas exposure groups: I: 70%/30% nitrogen/oxygen (control); II: 70%/30% helium/oxygen administered immediately after occlusion; III: 70%/30% helium/oxygen administered after a 30-60 min delay; or, IV: 40%/30%/30% nitrogen/helium/oxygen administered immediately after occlusion. Outcome measurements included infarct size and neurological deficit score. Mean infarct sizes from groups I to IV were 228, 35, 109, and 124 mm³ respectively (p=0.012). Only group II had significantly smaller infarct size compared to the control group (p=0.008). In addition, only Group II had a significantly lower neurological deficit score at 24h post ischemia when compared to the control group (p<0.001). Since heliox reduced infarct size and improved neurological deficit scores if initiated immediately after onset of ischemia, it may be a useful adjuvant to other stroke therapies.
    Neuroscience Letters 06/2011; 497(2):144-7. DOI:10.1016/j.neulet.2011.04.048 · 2.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Preconditioning is abolished in the prediabetic Zucker obese rat. It has been shown that prevention of mitochondrial permeability transition pore (mPTP) opening is involved in preconditioning by the noble gas helium. Here, we investigated: 1) whether helium induces pre- and postconditioning in Zucker rats and 2) whether possible regulators of the mPTP [i.e., mitochondrial respiration or the extracellular signal-regulated kinase (Erk) 1/2, Akt/glycogen synthase kinase (GSK)-3beta signaling pathway] are influenced. Anesthetized Zucker lean (ZL) and Zucker obese (ZO) rats were randomized to seven groups. Control animals were not treated (ZL-/ZO-Con). Preconditioning groups (ZL-/ZO-He-PC) inhaled 70% helium for 3 x 5 or 6 x 5 min, and postconditioning groups (ZL-/ZO-He-PostC) inhaled 70% helium for 15 min at the onset of reperfusion. Animals underwent 25 min of ischemia and 120 min of reperfusion. In additional experiments, hearts were excised after the third helium exposure for analysis of mitochondrial respiration and for Western blot analysis of Erk1/2, Akt, and GSK-3beta phosphorylation. Helium reduced infarct size from 52 +/- 3% (mean +/- S.E.) to 32 +/- 2% and 37 +/- 2% in ZL rats (ZL-HE-PC, ZL-He-PostC), respectively, but not in ZO rats [ZO-He-PC, 56 +/- 3%; ZO-He-PC (6x), 57 +/- 4%; and ZO-He-PostC, 51 +/- 3% versus ZO-Con, 54 +/- 3%]. Mitochondrial respiration analysis showed that helium causes mild uncoupling in ZL rats (2.27 +/- 0.03 versus 2.51 +/- 0.03) but not in ZO rats (2.52 +/- 0.04 versus 2.52 +/- 0.03). Helium had no effect on Erk1/2 and Akt phosphorylation. GSK-3beta phosphorylation during ischemia was reduced after helium application in ZL but not in ZO rats. Helium-induced preconditioning is abolished in obese Zucker rats in vivo, probably caused by a diminished effect of helium on mitochondrial respiration.
    Journal of Pharmacology and Experimental Therapeutics 03/2009; 329(2):600-7. DOI:10.1124/jpet.108.149971 · 3.86 Impact Factor
Show more