Signaling and cellular mechanisms in cardiac protection by ischemic and pharmacological preconditioning.
Ischemic preconditioning (IPC) is a defensive adaptive cellular phenomenon. Brief ischemic stimuli render the heart resistant to subsequent similar stress. Signaling for IPC and pharmacologically induced preconditioning involves several G-protein coupled cell surface receptors, second messengers, specific Ser-Thr-protein kinase-C isoforms, Tyr-kinases, and finally, results in activation of ATP-dependent potassium channels (inward rectifiers) at the sarcolemma and in the mitochondria. In cardiomyocytes these channels regulate cytosolic and mitochondrial Ca2+ levels. K+ influx into mitochondria proves to be a key factor for keeping the mitochondrial permeability transition pore closed. This ensures continuous energy production and prevents cell death by apoptosis or necrosis. Molecular structure, function, and pharmacological properties of the ATP-dependent potassium channels and of the mitochondrial permeability transition pore are discussed. Channel activating agents mimic IPC and also affect reactive oxygen species producing enzymes involved in mitochondrial respiration. Volatile anesthetics, among other drugs, mimic the cardioprotective effects of IPC. Their intracellular signaling and clinical application are briefly discussed.
Zaugg
Michael
M
Institute of Pharmacology and Toxicology, University of Zurich, Switzerland.
Schaub
Marcus C
MC
D000222:Adaptation, Physiological; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019610:Cytoprotection / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D009200:Myocardial Contraction / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000502:physiology; D009336:Necrosis; D015221:Potassium Channels; D015398:Signal Transduction / Q000502:physiology*
D000777:Anesthetics; D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel