Ischemic preconditioning: from adenosine receptor to KATP channel.
Ischemic preconditioning is a phenomenon whereby exposure of the myocardium to a brief episode of ischemia and reperfusion markedly reduces tissue necrosis induced by a subsequent prolonged ischemia. It is hoped that elucidation of the mechanism for preconditioning will yield therapeutic strategies capable of reducing myocardial infarction. In the rabbit, the brief period of preconditioning ischemia and reperfusion releases adenosine, bradykinin, opioids, and oxygen radicals. The combined effect of the release of these substances on G proteins and the cell's phospholipases induces the translocation and activation of the epsilon isozyme of protein kinase C. Protein kinase C appears to be the first element of a complex kinase cascade that is activated during the prolonged ischemia in preconditioned hearts. Current evidence indicates that this cascade contains at least one tyrosine kinase and ultimately leads to the activation of p38 mitogen-activated protein kinase. p38 Mitogen-activated protein kinase phosphorylates mitogen-activated protein kinase-activated protein kinase 2. Mitogen-activated protein kinase-activated protein kinase 2 phosphorylates HSP27, a 27-kDa heat shock protein that controls actin filament polymerization, and, therefore, affects the integrity of the cytoskeleton. Finally, mitochondrial adenosine 5'-triphosphate-sensitive K+ channels open, and the latter may be the final mediator of protection for ischemic preconditioning. The protective pathway has many built-in redundancies, perhaps creating a safety factor. These redundancies may also explain some of the species-related differences seen in ischemic preconditioning in which one redundant pathway may predominate over another.
Cohen
M V
MV
Department of Medicine, University of South Alabama, College of Medicine, Mobile 36688, USA. mcohen@usamail.usouthal.edu
Baines
C P
CP
Downey
J M
JM
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D054086:KATP Channels; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011817:Rabbits; D018047:Receptors, Purinergic P1 / Q000502:physiology*
D018528:ATP-Binding Cassette Transporters; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D018047:Receptors, Purinergic P1; C092520:uK-ATP-1 potassium channel