Extracellular signalling molecules in the ischaemic/reperfused heart – druggable and translatable for cardioprotection?

Abstract

In patients with acute myocardial infarction, timely reperfusion is essential to limit infarct size. However, reperfusion also adds to myocardial injury. Brief episodes of ischaemia/reperfusion in the myocardium or on organ remote from the heart, before or shortly after sustained myocardial ischaemia effectively reduce infarct size, provided there is eventual reperfusion. Such conditioning phenomena have been established in many experimental studies and also translated to humans. The underlying signal transduction, that is the molecular identity of triggers, mediators and effectors, is not clear yet in detail, but several extracellular signalling molecules, such as adenosine, bradykinin and opioids, have been identified to contribute to cardioprotection by conditioning manoeuvres. Several trials have attempted the translation of cardioprotection by such autacoids into a clinical scenario of myocardial ischaemia and reperfusion. Adenosine and its selective agonists reduced infarct size in a few studies, but this benefit was not translated into improved clinical outcome. All studies with bradykinin or drugs which increase bradykinin's bioavailability reported reduced infarct size and some of them also improved clinical outcome. Synthetic opioid agonists did not result in a robust infarct size reduction, but this failure of translation may relate to the cardioprotective properties of the underlying anaesthesia per se or of the comparator drugs. The translation of findings in healthy, young animals with acute coronary occlusion/reperfusion to patients of older age, with a variety of co-morbidities and co-medications, suffering from different scenarios of myocardial ischaemia/reperfusion remains a challenge. 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; AT1 receptor, angiotensin II type 1 receptor; CABG, coronary artery bypass surgery; eNOS/PKG, endothelial NOS/PKG; GLP, glucagon-like peptide; KATP, mitochondrial ATP-sensitive K + channel; MPTP, mitochondrial permeability transition pore; PCI, percutaneous coronary intervention; RIPC, remote ischaemic preconditioning; RISK, reperfusion injury salvage kinase; ROS, reactive oxygen species BJP British Journal of Pharmacology

The Coronary Circulation as a Target of Cardioprotection

“…Also, effective drug treatment (eg, by concomitant β-blockade, reninangiotensin system inhibition, statins, or P2Y 12 antagonists) may induce pre-existing cardioprotection and attenuate the consequences of acute myocardial ischemia/reperfusion. 35 In contrast to previous notions, the hemodynamic situation has little impact on the development of myocardial infarction; only heart rate determines infarct progression to some extent. 36 Variations in coronary blood flow not only determine the nature and extent of myocardial injury but paradoxically also protection from it.…”

“…As reviewed in detail elsewhere, 35,191,192 many exogenous agents and drugs which often rely on the recruitment of signal transduction steps of conditioning maneuvers 7 can reduce infarct size in various experimental models and in different species. In several such studies, the protection of the coronary circulation was also addressed.…”

Time to Give Up on Cardioprotection?

“…197 However, in a recent retrospective analysis for confounders, statin use even facilitated protection by remote ischemic perconditioning in patients with AMI. 180 Antihypertensive treatment with angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor antagonists may reduce infarct size and improve clinical outcome per se 198,199 (for review see Kleinbongard and Heusch 30 ), and these agents may also facilitate protection by conditioning interventions. 181,200 The same may be true for β-blockade, specifically for metoprolol, 201 but β-blockade may also abrogate the protection by conditioning interventions.…”

“…29 There are also numerous attempts to use single signaling molecules of the conditioning phenomena as drugs or drug targets to achieve cardioprotection. Although the intracardiac signal transduction of the conditioning phenomena seems largely similar, 28,30 the transfer factor(s) from the distant organ or tissue to the heart in remote ischemic conditioning is/are still enigmatic, but seem(s) to involve both neuronal and humoral signaling. There are obvious species differences in the signal transduction of the conditioning phenomena, and only little information is available on the signal transduction in the human heart: protein kinase C, 31,32 the reperfusion injury salvage kinase pathway, 33,34 the signal transducer and activator of transcription 5, 35 and the mitochondria 36 seem to be involved.…”

Molecular Basis of Cardioprotection

“…68,70 Carbon monoxide is synthetized by heme oxygenase, targets several cardioprotective signaling proteins, and reduces IS on exogenous administration; however, to date, there is no evidence for its role in the conditioning phenomena. 85 Bradykinin is cleaved from kininogen precursors in the interstitium and catabolized through the angiotensin-converting enzyme in the vasculature but also neutral endopeptidase in the interstitium. 86,87 During preconditioning ischemia/reperfusion cycle(s), the interstitial bradykinin concentration is rapidly increased, 71 and it activates the bradykinin receptor 2 subtype on cardiomyocytes, which couples to G i proteins and activates the downstream endothelial NOS/PKG and RISK pathways.…”