Inhibition of glycogen synthase kinase or the apoptotic protein p53 lowers the threshold of helium cardioprotection in vivo: the role of mitochondrial permeability transition.

Anesthesia and Analgesia
Paul S PagelDorothee Weihrauch

Abstract

Prosurvival signaling kinases inhibit glycogen synthase kinase-3beta (GSK-3beta) activity and stimulate apoptotic protein p53 degradation. Helium produces cardioprotection by activating prosurvival kinases, but whether GSK and p53 inhibition mediate this process is unknown. We tested the hypothesis that inhibition of GSK or p53 lowers the threshold of helium cardioprotection via a mitochondrial permeability transition pore (mPTP)-dependent mechanism. Rabbits (n = 85) 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), or 1, 3, or 5 cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture (fraction of inspired oxygen concentration = 0.30) before LAD occlusion. Other rabbits received the GSK inhibitor SB 216763 (SB21; 0.2 or 0.6 mg/kg), the p53 inhibitor pifithrin-alpha (PIF; 1.5 or 3.0 mg/kg), or SB21 (0.2 mg/kg) or PIF (1.5 mg/kg) plus helium (1 cycle) before LAD occlusion in the presence or absence of the mPTP opener atractyloside (5 mg/kg). Helium reduced (P < 0.05) myocardial infarct size (35 +/- 6 [n = 7], 25 +/- 4 [n = 7], and 20 +/- 3% [n = 6] of area at...Continue Reading

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Citations

Mar 20, 2009·British Journal of Anaesthesia·R HuhnB Preckel
Dec 8, 2011·Medical Gas Research·Wenwu LiuJohn H Zhang
Aug 7, 2013·Medical Gas Research·Carlos J Berganza, John H Zhang
May 27, 2009·Journal of Cardiothoracic and Vascular Anesthesia·Paul S Pagel
Feb 24, 2009·Journal of Cardiothoracic and Vascular Anesthesia·Paul S PagelDorothee Weihrauch
May 5, 2011·Neuroscience Letters·Yi PanW Michael Panneton
Apr 14, 2012·European Journal of Pharmacology·Gezina T M L OeiNina C Weber
May 13, 2010·Anesthesiology·Gezina T M L OeiBenedikt Preckel
Jan 18, 2019·Journal of Applied Physiology·Rongjia ZhangXuejun Sun
Oct 3, 2019·Scientific Reports·Xing YinShao-Ling Huang
Apr 17, 2009·Current Opinion in Anaesthesiology·Stefan G De HertWolfgang S Schlack
Dec 21, 2019·Intensive Care Medicine Experimental·Nina C Weber, Benedikt Preckel
Nov 5, 2014·British Journal of Pharmacology·Kirsten F SmitBenedikt Preckel
Mar 21, 2018·Journal of Cardiovascular Pharmacology and Therapeutics·Toshiyuki YanoCharles Steenbergen

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