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CARDIOVASCULAR ANESTHESIOLOGY

Inhibition of Glycogen Synthase Kinase or the Apoptotic Protein p53 Lowers the Threshold of Helium Cardioprotection In Vivo: The Role of Mitochondrial Permeability Transition

From the Anesthesia Service, the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin.

Address correspondence and reprint requests to Paul S. Pagel, MD, PhD, Clement J. Zablocki Veterans Affairs Medical Center, Anesthesia Service, 5000 W. National Ave., Milwaukee, WI 53295. Address e-mail to pspagel{at}mcw.edu.

Abstract

BACKGROUND: Prosurvival signaling kinases inhibit glycogen synthase kinase-3β (GSK-3β) 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.

METHODS: 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- (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).

RESULTS: Helium reduced (P < 0.05) myocardial infarct size (35 ± 6 [n = 7], 25 ± 4 [n = 7], and 20 ± 3% [n = 6] of area at risk, 1, 3, and 5 cycles, respectively) compared with control (44 ± 6% [n = 7]). SB21 (0.6 [n = 7] but not 0.2 mg/kg [n = 6]) and PIF (3.0 [n = 6] but not 1.5 mg/kg [n = 7]) also reduced necrosis. SB21 (0.2 mg/kg) or 1.5 mg/kg PIF (1.5 mg/kg) plus helium (1 cycle; n = 6 per group) decreased infarct size to an equivalent degree as three cycles of helium alone, and this cardioprotection was blocked by atractyloside (n = 7 per group).

CONCLUSIONS: Inhibition of GSK or p53 lowers the threshold of helium-induced preconditioning via a mPTP-dependent mechanism in vivo.

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				R. Huhn, A. Heinen, N. C. Weber, S. Hieber, M. W. Hollmann, W. Schlack, and B. Preckel Helium-induced late preconditioning in the rat heart in vivo Br. J. Anaesth., May 1, 2009; 102(5): 614 - 619. [Abstract] [Full Text] [PDF]

				P. S. Pagel and J. G. Krolikowski Transient Metabolic Alkalosis During Early Reperfusion Abolishes Helium Preconditioning Against Myocardial Infarction: Restoration of Cardioprotection by Cyclosporin A in Rabbits Anesth. Analg., April 1, 2009; 108(4): 1076 - 1082. [Abstract] [Full Text] [PDF]

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999