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Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection
Derek J Hausenloy1, Derek M Yellon
1The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, UK. hatter-institute@ucl.ac.uk
Insights
Targeting the Reperfusion Injury Salvage Kinase (RISK) pathway with specific agents during reperfusion therapy can protect the heart after acute myocardial infarction (AMI). Activating this pathway mimics natural protective mechanisms, offering a novel strategy to reduce heart damage.
Area of Science:
- Cardiovascular Medicine
- Molecular Cardiology
- Pharmacology
Background:
- Acute myocardial infarction (AMI) remains a leading cause of mortality and morbidity, often leading to heart failure.
- Current reperfusion strategies, while effective, have limitations in fully preventing myocardial damage and improving long-term outcomes.
- Novel cardioprotective strategies are needed to limit infarct size and preserve left ventricular function post-AMI.
Purpose of the Study:
- To review the Reperfusion Injury Salvage Kinase (RISK) pathway as a pharmacological target for cardioprotection during myocardial reperfusion.
- To explore various agents that activate the RISK pathway and their potential to mimic ischemic preconditioning and postconditioning.
- To discuss the clinical implications and future directions for using RISK pathway activators in AMI treatment.
Main Methods:
- Review of preclinical and preliminary clinical studies on the RISK pathway and its activators.
- Analysis of the mechanisms by which RISK pathway activation confers cardioprotection, including inhibition of mitochondrial permeability transition pore opening.
- Examination of the role of RISK pathway in ischemic preconditioning (IPC) and postconditioning (IPost).
Main Results:
- The RISK pathway, involving kinases like Akt and Erk1/2, is activated by various agents (e.g., insulin, erythropoietin, statins) during reperfusion, reducing infarct size.
- Activation of the RISK pathway recruits survival signaling cascades and inhibits cell death mechanisms.
- Pharmacological activation of the RISK pathway can mimic the cardioprotective effects of IPC and IPost.
- Preliminary clinical data suggest cardioprotection in AMI patients undergoing PCI with RISK pathway activators.
Conclusions:
- The RISK pathway represents a promising therapeutic target for cardioprotection in AMI.
- Pharmacological agents activating the RISK pathway offer a novel strategy to reduce myocardial infarct size and improve outcomes.
- Further well-designed clinical trials are warranted to confirm the efficacy of RISK pathway activators as adjuvant therapy in AMI patients undergoing reperfusion.
Abstract:
Following an acute myocardial infarction (AMI), early coronary artery reperfusion remains the most effective means of limiting the eventual infarct size. The resultant left ventricular systolic function is a critical determinant of the patient's clinical outcome. Despite current myocardial reperfusion strategies and ancillary antithrombotic and antiplatelet therapies, the morbidity and mortality of an AMI remain significant, with the number of patients developing cardiac failure increasing, necessitating the development of novel strategies for cardioprotection which can be applied at the time of myocardial reperfusion to reduce myocardial infarct size. In this regard, the Reperfusion Injury Salvage Kinase (RISK) Pathway, the term given to a group of pro-survival protein kinases (including Akt and Erk1/2), which confer powerful cardioprotection, when activated specifically at the time of myocardial reperfusion, provides an amenable pharmacological target for cardioprotection. Preclinical studies have demonstrated that an increasing number of agents including insulin, erythropoietin, adipocytokines, adenosine, volatile anesthetics natriuretic peptides and 'statins', when administered specifically at the time of myocardial reperfusion, reduce myocardial infarct size through the activation of the RISK pathway. This recruits various survival pathways that include the inhibition of mitochondrial permeability transition pore opening. Interestingly, the RISK pathway is also recruited by the cardioprotective phenomena of ischemic preconditioning (IPC) and postconditioning (IPost), enabling the use of pharmacological agents which target the RISK pathway, to be used at the time of myocardial reperfusion, as pharmacological mimetics of IPC and IPost. This article reviews the origins and evolution of the RISK pathway, as part of a potential common cardioprotective pathway, which can be activated by an ever-expanding list of agents administered at the time of myocardial reperfusion, as well as by IPC and IPost. Preliminary clinical studies have demonstrated myocardial protection with several of these pharmacological activators of the RISK pathway in AMI patients undergoing PCI. Through the use of appropriately designed clinical trials, guided by the wealth of existing preclinical data, the administration of pharmacological agents which are known to activate the RISK pathway, when applied as adjuvant therapy to current myocardial reperfusion strategies for patients presenting with an AMI, should lead to improved clinical outcomes in this patient group.
