title: The cGMP/PKG pathway as a common mediator of cardioprotection: translatability and mechanism.
abstract: Cardiomyocyte cell death occurring during myocardial reperfusion (reperfusion injury) contributes to final infarct size after transient coronary occlusion. Different interrelated mechanisms of reperfusion injury have been identified, including alterations in cytosolic Ca(2+) handling, sarcoplasmic reticulum-mediated Ca(2+) oscillations and hypercontracture, proteolysis secondary to calpain activation and mitochondrial permeability transition. All these mechanisms occur during the initial minutes of reperfusion and are inhibited by intracellular acidosis. The cGMP/PKG pathway modulates the rate of recovery of intracellular pH, but has also direct effect on Ca(2+) oscillations and mitochondrial permeability transition. The cGMP/PKG pathway is depressed in cardiomyocytes by ischaemia/reperfusion and preserved by ischaemic postconditioning, which importantly contributes to postconditioning protection. The present article reviews the mechanisms and consequences of the effect of ischaemic postconditioning on the cGMP/PKG pathway, the different pharmacological strategies aimed to stimulate it during myocardial reperfusion and the evidence, limitations and promise of translation of these strategies to the clinical practice. Overall, the preclinical and clinical evidence suggests that modulation of the cGMP/PKG pathway may be a therapeutic target in the context of myocardial infarction.
authors.affiliation: Cardiology Department, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Inserte
authors.forename: David
authors.initials: D
authors.lastname: Garcia-Dorado
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP