Ischemic postconditioning: from receptor to end-effector.

Abstract

Ischemic preconditioning, a robust cardioprotective intervention, has limited clinical efficacy because it must be initiated before myocardial ischemia. Conversely, ischemic postconditioning, repeated brief reocclusions of a coronary artery after release of prolonged coronary occlusion, provides cardioprotection in clinically feasible settings, that is, coronary angioplasty. Ischemic postconditioning's signaling is being investigated to identify pharmacological triggers that could be used without angioplasty. In initial minutes of reperfusion H(+) washes out of previously ischemic cells. pH rises enabling mitochondrial permeability transition pores (MPTPs) to form leading to cessation of ATP production and cell necrosis. Coronary reocclusions maintain sufficient acidosis to keep MPTP closed while signaling is initiated that can generate endogenous antagonists of MPTP formation even after cellular pH normalizes. Reintroduction of oxygen generates reactive oxygen species that activate protein kinase C to increase sensitivity of adenosine A(2b) receptors allowing adenosine released from ischemic cells to bind leading to activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2. Phosphatidylinositol 3-kinase activation results in phosphorylation of Akt promoting activation of nitric oxide synthase and nitric oxide production, which inhibits glycogen synthase kinase-3β, perhaps the final cytosolic signaling step before inhibition of MPTP formation. Interference with MPTP may be the final step that determines cell salvage.

• Authors: Michael V Cohen, James M Downey
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 14 Issue 5 Pg. 821-31 (Mar 01 2011) ISSN: 1557-7716 [Electronic] United States
• PMID: 20518705 (Publication Type: Journal Article, Review)

Chemical References

• Free Radical Scavengers
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Receptors, Purinergic P1
• Nitric Oxide
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Protein Kinase C
• Glycogen Synthase Kinase 3

Topics

• Animals
• Free Radical Scavengers (pharmacology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Hydrogen-Ion Concentration
• Ischemic Postconditioning
• Ischemic Preconditioning, Myocardial
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Permeability Transition Pore
• Myocardial Infarction (metabolism)
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• Nitric Oxide (metabolism, pharmacology)
• Oxidation-Reduction
• Protein Kinase C (metabolism)
• Receptors, Purinergic P1 (metabolism)
• Signal Transduction (drug effects)