Differential activation of mitogen-activated protein kinases in ischemic and anesthetic preconditioning.

Abstract

BACKGROUND:

Accumulating evidence pinpoints to the pivotal role of mitogen-activated protein kinases (MAPKs) in the signal transduction underlying cardiac preconditioning.

METHODS:

PD98059, an inhibitor of extracellular signal-regulated protein kinase (MEK-ERK1/2), and SB203580, an inhibitor of p38 MAPK, were used to evaluate the role of MAPKs with respect to postischemic functional recovery in isolated perfused rat hearts subjected to ischemic preconditioning (IPC) and anesthetic preconditioning (APC). Western blot analyses were used to determine the degree of ERK1/2 and p38 MAPK activation after the application of the preconditioning stimulus and after ischemia-reperfusion. Immunohistochemical staining served to visualize subcellular localization of activated MAPKs.

RESULTS:

PD98059 and SB203580 abolished postischemic functional recovery in IPC but not in APC. IPC but not APC markedly activated ERK1/2 and p38 MAPK, which were abrogated by coadministration of the specific blockers. Conversely, IPC and APC enhanced ERK1/2 activity after ischemia-reperfusion as compared to nonpreconditioned hearts, and IPC in addition enhanced p38 MAPK activity. Coadministration of PD98059 and SB203580 during IPC but not during APC inhibited postischemically enhanced MAPK activities. Moreover, chelerythrine and 5-hydroxydecanoate, effective blockers of IPC and APC, annihilated IPC- and APC-induced enhanced postischemic responses of MAPKs. Finally, administration of PD98059 during ischemia-reperfusion diminished the protective effects of IPC and APC. Immunohistochemistry revealed increased ERK1/2 activity primarily in intercalated discs and nuclei and increased p38 MAPK activity in the sarcolemma and nuclei of IPC-treated hearts.

CONCLUSIONS:

Although MAPKs may orchestrate cardioprotection as triggers and mediators in IPC, they are devoid of triggering, but they may have mediator effects in APC.

• Authors: Rafaela da Silva, Thomas Grampp, Thomas Pasch, Marcus C Schaub, Michael Zaugg
• Journal: Anesthesiology (Anesthesiology) Vol. 100 Issue 1 Pg. 59-69 (Jan 2004) ISSN: 0003-3022 [Print] United States
• PMID: 14695725 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics
• Heat-Shock Proteins
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Anesthetics (pharmacology)
• Animals
• Blotting, Western
• Enzyme Activation (physiology)
• Heart (drug effects, physiology)
• Heat-Shock Proteins (metabolism)
• Immunohistochemistry
• In Vitro Techniques
• Ischemic Preconditioning, Myocardial
• Male
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (metabolism)
• Myocardium (enzymology)
• Phenotype
• Rats
• Rats, Wistar
• Reperfusion Injury (pathology)
• p38 Mitogen-Activated Protein Kinases