Faculty Collaboration Database

Xenon preconditioning: the role of prosurvival signaling, mitochondrial permeability transition and bioenergetics in rats. Anesth Analg 2009 Mar;108(3):858-66

Date

02/20/2009

Pubmed ID

19224794

Pubmed Central ID

PMC2748301

DOI

10.1213/ane.0b013e318192a520

Scopus ID

2-s2.0-61949171919 (requires institutional sign-in at Scopus site)   54 Citations

Abstract

BACKGROUND: Similar to volatile anesthetics, the anesthetic noble gas xenon protects the heart from ischemia/reperfusion injury, but the mechanisms responsible for this phenomenon are not fully understood. We tested the hypothesis that xenon-induced cardioprotection is mediated by prosurvival signaling kinases that target mitochondria.

METHODS: Male Wistar rats instrumented for hemodynamic measurements were subjected to a 30 min left anterior descending coronary artery occlusion and 2 h reperfusion. Rats were randomly assigned to receive 70% nitrogen/30% oxygen (control) or three 5-min cycles of 70% xenon/30% oxygen interspersed with the oxygen/nitrogen mixture administered for 5 min followed by a 15 min memory period. Myocardial infarct size was measured using triphenyltetrazolium staining. Additional hearts from control and xenon-pretreated rats were excised for Western blotting of Akt and glycogen synthase kinase 3 beta (GSK-3beta) phosphorylation and isolation of mitochondria. Mitochondrial oxygen consumption before and after hypoxia/reoxygenation and mitochondrial permeability transition pore opening were determined.

RESULTS: Xenon significantly (P < 0.05) reduced myocardial infarct size compared with control (32 +/- 4 and 59% +/- 4% of the left ventricular area at risk; mean +/- sd) and enhanced phosphorylation of Akt and GSK-3beta. Xenon pretreatment preserved state 3 respiration of isolated mitochondria compared with the results obtained in the absence of the gas. The Ca(2+) concentration required to induce mitochondrial membrane depolarization was larger in the presence compared with the absence of xenon pretreatment (78 +/- 17 and 56 +/- 17 microM, respectively). The phosphoinositol-3-kinase-kinase inhibitor wortmannin blocked the effect of xenon on infarct size and respiration.

CONCLUSIONS: These results indicate that xenon preconditioning reduces myocardial infarct size, phosphorylates Akt, and GSK-3beta, preserves mitochondrial function, and inhibits Ca(2+)-induced mitochondrial permeability transition pore opening. These data suggest that xenon-induced cardioprotection occurs because of activation of prosurvival signaling that targets mitochondria and renders them less vulnerable to ischemia-reperfusion injury.

Author List

Mio Y, Shim YH, Richards E, Bosnjak ZJ, Pagel PS, Bienengraeber M

MESH terms used to index this publication - Major topics in bold

Anesthetics, Inhalation
Animals
Blood Pressure
Blotting, Western
Calcium
Cardiotonic Agents
Energy Metabolism
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Heart Rate
Ischemic Preconditioning, Myocardial
Male
Mitochondria, Heart
Myocardial Infarction
Myocardial Reperfusion Injury
Oxygen Consumption
Permeability
Phosphorylation
Proto-Oncogene Proteins c-akt
Rats
Rats, Wistar
Xenon