Circulating mediators of remote ischemic preconditioning: search for the missing link between non-lethal ischemia and cardioprotection

Abstract

Acute myocardial infarction (AMI) is one of the leading causes of mortality and morbidity worldwide. There has been an extensive search for cardioprotective therapies to reduce myocardial ischemia-reperfusion (I/R) injury. Remote ischemic preconditioning (RIPC) is a phenomenon that relies on the body's endogenous protective modalities against I/R injury. In RIPC, non-lethal brief I/R of one organ or tissue confers protection against subsequent lethal I/R injury in an organ remote to the briefly ischemic organ or tissue. Initially it was believed to be limited to direct myocardial protection, however it soon became apparent that RIPC applied to other organs such as kidney, liver, intestine, skeletal muscle can reduce myocardial infarct size. Intriguing discoveries have been made in extending the concept of RIPC to other organs than the heart. Over the years, the underlying mechanisms of RIPC have been widely sought and discussed. The involvement of blood-borne factors as mediators of RIPC has been suggested by a number of research groups. The main purpose of this review article is to summarize the possible circulating mediators of RIPC, and recent studies to establish the clinical efficacy of these mediators in cardioprotection from lethal I/R injury.

Remote Ischemic Preconditioning Induces Cardioprotective Autophagy and Signals through the IL-6-Dependent JAK-STAT Pathway

“…However, Gedik and colleagues did not detect any significant change in IL-6 levels in arterial plasma sample collected after RIPC from patients undergoing elective CABG [74]. Age, presence of co-morbidity, medications, anesthetic regimen, and extent of preconditioning stimuli may all interfere with the cardioprotective modalities of RIPC [13] and may explain the discrepancy with our findings. In addition, the timing of sampling may have interfered with the detection of IL-6 protein after RIPC stimuli.…”

“…Myocardial reperfusion injury is a dynamic injury with peak myeloperoxidase (MPO) activity and endothelial dysfunction at 24 h [64]. RIPC has two windows of protection: A first or early window of protection opens within minutes of RIPC stimulus and remains open for 4-5 h, whereas the second window of protection opens at a later time point after RIPC stimulus and remains open for some days [13]. Autophagy was regarded as being involved in non-apoptotic programmed cell death and was considered a doubled-edged sword in cell survival [65,66].…”

“…Daily use of RIPC prevented cardiac remodeling after acute myocardial infarction (AMI) [12], suggesting a prolonged beneficial effect beyond infarct size reduction. A large number of clinical trials have investigated the clinical efficacy of RIPC, with varied results [13]. As an adjunct therapy to standard patient care, RIPC has been demonstrated to reduce cardiac mortality and hospitalization for heart failure patients [14], and improves the myocardial salvage index [15] in ST-elevation myocardial infarction (STEMI) patients.…”

“…As experimental animal models with comorbidity usually does not receive multiple medications for the underlying comorbidity [17], it is difficult to translate the experimental findings to clinical settings. We have previously summarized the effect of RIPC on PCI and coronary artery bypass grafting (CABG) patients [13].An understanding of the signaling mechanism would be an attractive pharmacological target to be reinforced in situations where cardioprotection is required, such as MI, CABG, and PCI.Autophagy is a cellular process by which mammalian cells degrade and recycle damaged organelles and proteins [18]. In the heart, autophagy plays a major role in maintaining intracellular homeostasis.…”

“…As experimental animal models with comorbidity usually does not receive multiple medications for the underlying comorbidity [17], it is difficult to translate the experimental findings to clinical settings. We have previously summarized the effect of RIPC on PCI and coronary artery bypass grafting (CABG) patients [13].…”