Postconditioning signalling in the heart: mechanisms and translatability

Abstract

The protective effect of ischaemic postconditioning (short cycles of reperfusion and reocclusion of a previously occluded vessel) was identified over a decade ago commanding intense interest as an approach for modifying reperfusion injury which contributes to infarct size in acute myocardial infarction. Elucidation of the major mechanisms of postconditioning has identified potential pharmacological targets for limitation of reperfusion injury. These include ligands for membrane-associated receptors, activators of phosphokinase survival signalling pathways and inhibitors of the mitochondrial permeability transition pore. In experimental models, numerous agents that target these mechanisms have shown promise as postconditioning mimetics. Nevertheless, clinical studies of ischaemic postconditioning and pharmacological postconditioning mimetics are equivocal. The majority of experimental research is conducted in animal models which do not fully portray the complexity of risk factors and comorbidities with which patients present and which we now know modify the signalling pathways recruited in postconditioning. Cohort size and power, patient selection, and deficiencies in clinical infarct size estimation may all represent major obstacles to assessing the therapeutic efficacy of postconditioning. Furthermore, chronic treatment of these patients with drugs like ACE inhibitors, statins and nitrates may modify signalling, inhibiting the protective effect of postconditioning mimetics, or conversely induce a maximally protected state wherein no further benefit can be demonstrated. Arguably, successful translation of postconditioning cannot occur until all of these issues are addressed, that is, experimental investigation requires more complex models that better reflect the clinical setting, while clinical investigation requires bigger trials with appropriate patient selection and standardization of clinical infarct size measurements. LINKED ARTICLESThis article is part of a themed section on Conditioning the Heart -Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-8 Abbreviations AMI, acute myocardial infarction; CK, creatine kinase; CK-MB, creatine kinase assay; CYP-D, cyclophilin-D; Cys-A, cyclosporine-A; eNOS, endothelial NOS; EPO, erythropoietin; GSK-3β, glycogen synthase-3β; MKATP, ATP-sensitive mitochondrial potassium channel; MPTP, mitochondrial permeability transition pore; PCI, percutaneous coronary intervention; RISK, reperfusion injury salvage kinase; ROS, reactive oxygen species; SAFE, survivor activating factor enhancement Development of the postconditioning paradigm for cardioprotectionDeath due to acute myocardial infarction (AMI) has declined steadily in the economically developed countries during the last 50 years. Since the 1980s, the development of reperfusion therapies as the 'standard of care' for AMI has contributed markedly to the decline in early mortality. However, while case fatality rate has declined, there is evidence of an in...

The Interplay between the Renin Angiotensin System and Pacing Postconditioning Induced Cardiac Protection

“…Henceforth care must be taken when planning studies including this group of patients. Drug interference with postconditioning maneuvers was reported in patients with acute coronary syndrome and was suggested to interfere with postconditioning afforded protection [53], [54]. Our data further suggests that blockade of endogenously synthesized Ang II by captopril or chymostatin post-ischemically might represent a novel pharmacological alternative to PPC for the treatment of myocardial I/R injury as the attained cardioprotection was comparable to that of PPC.…”

Application of ischemic postconditioning's algorithms in tissues protection: response to methodological gaps in preclinical and clinical studies

“…The proposed mechanisms of actions of IPostC in the literature indicate that the protective effect of IPostC is essentially associated with reversing the reperfusion‐induced pathologies including oxidative stress, intracellular calcium overload, endothelial dysfunction and inflammatory responses . The most crucial finding is that the signalling pathways activated by IPostC during the initial minutes of reperfusion ultimately lead to the blockade of the mitochondrial permeability transition pores (mPTP), which its opening is a critical event leading to the cell death during reperfusion . Three separate signalling pathways for IPostC actions have been proposed: (1) reperfusion injury salvage kinase (RISK) pathway that includes the activation of PI3K/Akt and ERK and eventually inhibition of GSK‐3β; (2) survivor activating factor enhancement (SAFE) pathway that JAK/STAT and TNF‐α are the main components of this pathway; and (3) cGMP/PKG as a supplementary pathway, in which activation of natriuretic peptides and soluble guanylyl cyclase leading to the opening of mitochondrial ATP‐sensitive potassium channels.…”

Rapid ventricular pacing‐induced postconditioning attenuates reperfusion injury: effects on peroxynitrite, RISK and SAFE pathways

“…Taken together, our present results indicate that (i) the downstream mechanisms of RVP-induced cardioprotection and IPost are partially different; (ii) HO1 is probably not involved in the cardioprotective effect of RVPinduced postconditioning; and (iii) the precise role of the RISK and SAFE pathways remains to be elucidated in future studies. The involvement of alternative pathways in the protective effect of RVP-induced postconditioning is likely and may include, for instance, activation of NO-cGMP-PKG, sphingosine-, PKC-or CGRP-mediated pathways (Heusch et al, 2008;Bice and Baxter, 2014). Since endogenous NO-cGMP plays a role in protection against reperfusion injury by attenuating infarct size (Penna et al, 2006) and…”