Delayed adaptation of the heart to stress: late preconditioning

Abstract

The early phase of preconditioning (PC) lasts 2 to 3 hours and protects against myocardial infarction, but not against stunning. In contrast, the late phase of PC lasts for 3 to 4 days and protects against both myocardial stunning and infarction, making this phenomenon more clinically relevant. Late PC is a genetic reprogramming of the heart that involves the activation of several stress-responsive genes, which ultimately results in the development of a cardioprotective phenotype. Sublethal ischemic insults release chemical signals (nitric oxide [NO], adenosine, and reactive oxygen species) that trigger a series of signaling events (eg, activation of protein kinase C, Src protein tyrosine kinases, Janus kinases 1/2, and nuclear factor-kappaB) and culminates in increased synthesis of inducible NO synthase, cyclooxygenase-2, heme oxygenase-1, aldose reductase, Mn superoxide dismutase, and probably other cardioprotective proteins. In addition to ischemia, heat stress, exercise, and cytokines can also induce a similar series of events. Perhaps most importantly, many pharmacologic agents (eg, NO donors, adenosine receptor agonists, endotoxin derivatives, or opioid receptor agonists) can mimic the effects of ischemia in inducing the late phase of PC, suggesting that this phenomenon might be exploited therapeutically. The purpose of this review is to summarize the mechanisms that underlie the late phase of ischemic PC.

Figure

Schematic representation of the cellular mechanisms underlying late PC. Physical stress (eg, reversible ischemia, heat stress, ventricular pacing, exercise, or hypoxia) causes release of chemical signals (NO, ROS, adenosine, and possibly catecholamine or opioid-like substance) that serve as triggers for the development of late PC. These substances activate a complex signal transduction cascade that includes PKC (specifically, the ε isoform), PTKs (specifically, Src and/or Lck), Janus kinases (JAKs; specifically, JAK1 and JAK2) and probably other as-yet-unknown kinases. The recruitment of PKC, JAKs, and distal kinases leads to activation of NF-κB, STATs, and almost certainly other transcription factors, resulting in increased transcription of multiple cardioprotective genes and synthesis of multiple cardioprotective proteins that serve as comediators of protection 2 to 4 days after the PC stimulus.