Noble Gases Without Anesthetic Properties Protect Myocardium Against Infarction by Activating Prosurvival Signaling Kinases and Inhibiting Mitochondrial Permeability Transition In Vivo

Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin, United States
Anesthesia and analgesia (Impact Factor: 3.47). 09/2007; 105(3):562-9. DOI: 10.1213/01.ane.0000278083.31991.36
Source: PubMed


The anesthetic noble gas, xenon, produces cardioprotection. We hypothesized that other noble gases without anesthetic properties [helium (He), neon (Ne), argon (Ar)] also produce cardioprotection, and further hypothesized that this beneficial effect is mediated by activation of prosurvival signaling kinases [including phosphatidylinositol-3-kinase, extracellular signal-regulated kinase, and 70-kDa ribosomal protein s6 kinase] and inhibition of mitochondrial permeability transition pore (mPTP) opening in vivo.
Rabbits (n = 98) instrumented for hemodynamic measurement and subjected to a 30-min left anterior descending coronary artery (LAD) occlusion and 3 h reperfusion received 0.9% saline (control), three cycles of 70% He-, Ne-, or Ar-30% O2 administered for 5 min interspersed with 5 min of 70% N2-30% O2 before LAD occlusion, or three cycles of brief (5 min) ischemia interspersed with 5 min reperfusion before prolonged LAD occlusion and reperfusion (ischemic preconditioning). Additional groups of rabbits received selective inhibitors of phosphatidylinositol-3-kinase (wortmannin; 0.6 mg/kg), extracellular signal-regulated kinase (PD 098059; 2 mg/kg), or 70-kDa ribosomal protein s6 kinase (rapamycin; 0.25 mg/kg) or mPTP opener atractyloside (5 mg/kg) in the absence or presence of He pretreatment.
He, Ne, Ar, and ischemic preconditioning significantly (P < 0.05) reduced myocardial infarct size [23% +/- 4%, 20% +/- 3%, 22% +/- 2%, 17% +/- 3% of the left ventricular area at risk (mean +/- sd); triphenyltetrazolium chloride staining] versus control (45% +/- 5%). Wortmannin, PD 098059, rapamycin, and atractyloside alone did not affect infarct size, but these drugs abolished He-induced cardioprotection.
The results indicate that noble gases without anesthetic properties produce cardioprotection by activating prosurvival signaling kinases and inhibiting mPTP opening in rabbits.

    • "(Soldatov et al. 1998) Argon has been subjected to a series of models of organ dysfunction or injury, aiming toward protection at different levels. Argon may protect organs such as kidneys and heart (Preckel et al. 2006; Pagel et al. 2007; Rizvi et al. 2010; Irani et al. 2011) as well as neuronal cells through anti-inflammatory effects possibly including GABA and NMDA receptors in a model of experimental brain injury. (Abraini et al. 2003; Dickinson and Franks 2010; Ryang et al. 2011; Coburn and Rossaint 2012; David et al. 2012; Zhuang et al. 2012; Alderliesten et al. 2014) Recently, we demonstrated that Argon inhalation exerts neuroprotective effects after retinal IRI (R-IRI) by reducing apoptosis in a time-and dose-dependent manner. "
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    ABSTRACT: Retinal ischemia and reperfusion injuries (R-IRI) damage neuronal tissue permanently. Recently, we demonstrated that Argon exerts anti-apoptotic and protective properties. The molecular mechanism remains unclear. We hypothesized that Argon inhalation exert neuroprotective effects in rats retinal ganglion cells (RGC) via an ERK-1/2 dependent regulation of heat shock proteins. Inhalation of Argon (75 Vol%) was performed after R-IRI on the rats' left eyes for 1 hour immediately or with delay. Retinal tissue was harvested after 24 hours to analyze mRNA and protein expression of heat shock proteins -70, -90 and heme-oxygenase-1, mitogen-activated protein kinases (p38, JNK, ERK-1/2) and histological changes. To analyze ERK dependent effects, the ERK inhibitor PD98059 was applicated prior to Argon inhalation. RGC count was analyzed 7 days after injury. Statistics were performed using ANOVA. Argon significantly reduced the R-IRI-affected heat shock protein expression (p<0.05). While Argon significantly induced ERK-1/2 expression (p<0.001), inhibition of ERK-1/2 before Argon inhalation resulted in significantly lower vital RGCs (p<0.01) and increase of heme-oxygenase-1 (p<0.05). R-IRI-induced RGC loss was reduced by Argon inhalation (p<0.001). Immunohistochemistry suggested ERK-1/2 activation in Müller cells. We conclude, that Argon treatment protects R-IRI-induced apoptotic loss of RGC via an ERK-1/2 dependent regulation of heme-oxygenase-1. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Apr 2015 · Journal of Neurochemistry
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    • "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]. "
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    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 A2A 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.
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    • "Inhalation of hydrogen gas has been shown to limit infarct size following I/R injury in rat and in canine hearts via opening of mitochondrial KATP channels followed by inhibition of mitochondria permeability transition pore opening (mPTP) (Yoshida et al., 2012). The noble gas helium (He) is capable of inducing early and late PC at concentrations of 70 and 30%, respectively, by prevention of mPTP opening (Pagel et al., 2007; Huhn et al., 2009). However, the majority of research conducted to date has examined the cardioprotective effects of xenon because this noble gas exerts anaesthetic and analgesic effects under normal (as opposed to hyperbaric) atmospheric pressure conditions. "
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    Full-text · Article · Jun 2014 · British Journal of Pharmacology
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