Mechanisms of xenon- and isoflurane-induced preconditioning - a potential link to the cytoskeleton via the MAPKAPK-2/HSP27 pathway.
We previously demonstrated that the anesthetic gas xenon exerts cardioprotection by preconditioning in vivo via activation of protein kinase C (PKC)-epsilon and p38 mitogen-activated protein kinase (MAPK). P38 MAPK interacts with the actin cytoskeleton via the MAPK-activated protein kinase-2 (MAPKAPK-2) and heat-shock protein 27 (HSP27). The present study further elucidated the underlying molecular mechanism of xenon-induced preconditioning (Xe-PC) by focusing on a potential link of xenon to the cytoskeleton. Anesthetized rats received either xenon (Xe-PC, n = 6) or the volatile anesthetic isoflurane (Iso-PC, n = 6) during three 5-min periods interspersed with two 5-min and one final 10-min washout period. Control rats (n = 6) remained untreated for 45 min. Additional rats were either pretreated with the PKC inhibitor Calphostin C (0.1 mg kg(-1)) or with the p38 MAPK inhibitor SB203580 (1 mg kg(-1)) with and without anesthetic preconditioning (each, n = 6). Hearts were excised for immunohistochemistry of F-actin fibers and phosphorylated HSP27. Phosphorylation of MAPKAPK-2 and HSP27 were assessed by Western blot. HSP27 and actin colocalization were investigated by co-immunoprecipitation. Xe-PC induced phosphorylation of MAPKAPK-2 (control 1.0 +/- 0.2 vs Xe-PC 1.6 +/- 0.1, P < 0.05) and HSP27 (control 5.0 +/- 0.5 vs Xe-PC 9.8 +/- 1.0, P < 0.001). Both effects were blocked by Calphostin C and SB203580. Xe-PC enhanced translocation of HSP27 to the particulate fraction and increased F-actin polymerization. F-actin and pHSP27 were colocalized after Xe-PC. Xe-PC activates MAPKAPK-2 and HSP27 downstream of PKC and p38 MAPK. These data link Xe-PC to the cytoskeleton, revealing new insights into the mechanisms of Xe-PC in vivo.
Weber
Nina C
NC
Department of Anesthesiology, University Hospital of Düsseldorf, Germany. Nina.Weber@uni-duesseldorf.de
Toma
Octavian
O
Wolter
Jessica I
JI
Wirthle
Nicole M
NM
Schlack
Wolfgang
W
Preckel
Benedikt
B
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D019157:Ischemic Preconditioning, Myocardial; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014978:Xenon / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D018685:Anesthetics, Inhalation; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007530:Isoflurane; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D014978:Xenon; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C486114:Hspb1 protein, rat