© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Cytokines and Late Preconditioning*
Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Bethesda 20892-7940, USA
* Tel.: +1 301 435 0516; fax: +1 301 480 1454. E-mail address: db225a{at}nih.gov
Received 20 July 2004; accepted 26 July 2004
See article by Dawn et al. [7] (pages 61–71) in this issue.
It is now almost two decades since the first reports of ischemic preconditioning, the induction of cardiac tolerance to ischemic stress by a sublethal period of ischemia [1]. In the early 1990s, these findings were extended to show that preconditioning is a biphasic phenomenon; an early phase of preconditioning develops within minutes and lasts for 2 to 3 h, while a late phase is delayed until 12–24 h after the ischemic stress and lasts for 3 to 4 days [2,3]. In contrast to the early or "classic" phase of preconditioning, the heart is also protected against stunning during the late phase [4].
The late or delayed phase of ischemic preconditioning has attracted considerable attention because it holds the promise of clinically relevant manipulations that could be cardioprotective in patients with chronic ischemic heart disease. A large body of work has contributed to unraveling many of the mechanistic secrets that underlie late preconditioning. Stress signals, both ischemic and non-ischemic, activate signaling pathways that in turn lead to the activation of transcription factors. Transcriptional activation results in the synthesis of a number of protein effectors of late preconditioning, including inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX 2), aldose reductase, and mitochondrial manganese superoxide dismutase (Mn-SOD) [4,5]. Late preconditioning requires the parallel induction of multiple effectors, and blockade of synthesis of any of the effectors can abolish the cardioprotective effects of late preconditioning. The preconditioned phenotype thus requires the induction of an armamentarium of defensive mechanisms to protect against the stresses of ischemia and infarction.
The JAK–STAT (Janus kinase–signal transducers and activators of transcription) pathway has been shown previously to be essential for preconditioning [6]. However, the stimulus responsible for activation of the JAK–STAT pathway in late preconditioning was unclear. The study by Dawn et al. [7] in this issue elegantly demonstrates that interleukin-6 (IL-6), which has been previously shown to be released following myocardial injury, plays an essential role in activating late preconditioning. Using IL-6–/– mice, they showed that the absence of IL-6 did not affect infarct size in non-preconditioned mice, but completely abrogated the infarct-sparing effect of ischemic preconditioning. The loss of the preconditioning effect in IL-6–/– mice paralleled a marked attenuation of activation of the JAK–STAT pathway and decreased induction of iNOS and COX-2. However, other stimuli must contribute to the activation of JAK–STAT, since residual activation of the JAK–STAT pathway occurred even in IL-6–/– mice.
The demonstration of an obligatory role for IL-6 in late preconditioning provides a further link between cytokine signaling and the late phase of cardioprotection. It has previously been shown that tumor necrosis factor alpha (TNF-
) and interleukin-1β (IL-1β) are also involved in the late phase of cardiac preconditioning. Infusion of TNF- or IL-1β into mice resulted in biphasic protection of the heart against ischemia-reperfusion, similar to that observed with sublethal stresses such as brief ischemia, hyperthermia, or exercise [8,9]. Cytokine infusion resulted in expression of the radical scavenger Mn-SOD and induction of late preconditioning. Infusion of antioxidant blocked both Mn-SOD expression and late preconditioning, indicating a role for reactive oxygen species in the induction pathway. In parallel, in mice preconditioned by brief cardiac ischemia, hyperthermia, or exercise, neutralizing antibodies to TNF- and IL-1β blocked induction of Mn-SOD and abolished the late phase of preconditioning. In this case, there appears to be redundancy in the signaling pathways, since administration of the antibodies in combination was required; neither antibody alone was sufficient to block induction of Mn-SOD and cardioprotection.
Proinflammatory cytokines, such as IL-1β, IL-6, and TNF-, are not expressed constitutively in the normal heart, but are up-regulated rapidly during infarction in response to both ischemia and mechanical stretch [10]. Reactive oxygen species and cytokine self-amplification pathways also contribute to cytokine production. Plasma concentrations of inflammatory cytokines are elevated in patients with atherosclerosis, and for IL-6, in particular, plasma levels are correlated with risk of myocardial infarction [11]. High levels of IL-6 and TNF- were also shown to be strongly associated with the incidence of cardiovascular events in elderly patients who had no evidence of heart disease at study enrollment [12]. Cytokines have pleiotropic effects in the heart, which can have both positive and negative consequences on outcomes following infarction. Inflammatory cytokines decrease cardiac contractility, which may have a cardioprotective effect in the setting of acute injury [10]. Other beneficial effects of cytokines in the acute post-infarction period include contribution to stimulation of myocyte hypertrophy and initiation of wound healing [10]. In the chronic post-infarction period, levels of pro-inflammatory cytokines usually return towards baseline, but for large infarctions or in the presence of additional stress factors, a cycle of cytokine self-amplification spreading to the non-infarcted zone can promote interstitial fibrosis and collagen deposition, ultimately contributing to the development of dilated cardiomyopathy [10].
While progress has been made in understanding the mechanisms underlying late preconditioning, the clinical significance of the phenomenon remains unclear, reflecting the complexities of clinical research. Pre-infarct angina occurring 24–72 h prior to myocardial infarction is associated with improved outcomes, including lower mortality, lower peak creatine kinase levels, and better contractile function [13]. However, a caveat in interpreting clinical studies is the difficulty of distinguishing between enhanced recruitment of collaterals in response to ischemic insults and ischemic preconditioning of the myocardium. A recent study showed that exercise-induced ischemia induces late preconditioning independent of collateral recruitment. Patients with stable angina undergoing a second exercise tolerance test 24 h after the first test increased their ischemic threshold and decreased ventricular ectopic frequency; intracoronary pressure-derived coronary flow index measurements suggested that recruitment of collaterals was not responsible [14]. Myocardial preconditioning induced by exercise or by nitroglycerin was also shown to improve hemodynamics in patients with chronic stable angina [15].
There is thus a growing body of evidence to support the occurrence of late preconditioning in patients with angina. However, the mechanism(s) by which late preconditioning is induced in humans, and the potential role of cytokines in this induction, is currently unclear. IL-6 is produced locally in working human skeletal muscle, resulting in an increase in plasma IL-6 [16], while myocardial TNF- production is induced rapidly by hemodynamic stretch in feline heart [17]. It is thus feasible that cytokines may contribute to exercise-induced late preconditioning in patients with coronary artery disease. However, the importance of exercise-induced cytokine production and signaling in induction of late preconditioning, particularly in the context of elevated pro-inflammatory cytokines in patients, remains to be determined. Chronic exposure to elevated cytokines could result in tachyphylaxis, blunting the cardioprotective response to cytokines produced in response to stress stimuli.
In summary, the up-regulation of pro-inflammatory cytokines plays an important role in induction of the late phase of ischemic preconditioning in rodent models. While a number of studies suggest that late preconditioning also occurs in human myocardium, the mechanisms involved are unknown. Determining the role of cytokine signaling in induction of late preconditioning in humans will be important, since elevations in plasma cytokines in patients could impact responses to preconditioning stimuli.
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No conflict of interest to disclose.
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References |
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 Top References |
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- Murry C.E., Jennings R.B., Reimer K.A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation (1986) 74:1124–1136.
[Abstract/Free Full Text] - Kuzuya T., Hoshida S., Yamashita N., et al. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ. Res. (1993) 72:1293–1299.
[Abstract/Free Full Text] - Marber M.S., Latchman D.S., Walker J.M., Yellon D.M. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation (1993) 88:1264–1272.
[Abstract/Free Full Text] - Bolli R. The late phase of preconditioning. Circ. Res. (2000) 87:972–983.
[Abstract/Free Full Text] - Yellon D.M., Downey J.M. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol. Rev. (2003) 83:1113–1151.
[Abstract/Free Full Text] - Xuan Y.T., Guo Y., Han H., et al. An essential role of the JAK–STAT pathway in ischemic preconditioning. Proc. Natl. Acad. Sci. U. S. A. (2001) 98:9050–9055.
[Abstract/Free Full Text] - Dawn B., Xuan Y.-T., Guo Y., et al. IL-6 plays an obligatory role in late preconditioning via JAK–STAT signaling and upregulation of iNOS and COX-2. Cardiovasc. Res. (2004) 64:61–71.
[Abstract/Free Full Text] - Hoshida S., Yamashita N., Otsu K., Hori M. Repeated physiologic stresses provide persistent cardioprotection against ischemia-reperfusion injury in rats. J. Am. Coll. Cardiol. (2002) 40:826–831.
[Abstract/Free Full Text] - Hoshida S., Yamashita N., Otsu K., Hori M. The importance of manganese superoxide dismutase in delayed preconditioning: involvement of reactive oxygen species and cytokines. Cardiovasc. Res. (2002) 55:495–505.
[Abstract/Free Full Text] - Nian M., Lee P., Khaper N., Liu P. Inflammatory cytokines and postmyocardial infarction remodeling. Circ. Res. (2004) 94:1543–1553.
[Abstract/Free Full Text] - Bennet A.M., Prince J.A., Fei G.Z., et al. Interleukin-6 serum levels and genotypes influence the risk for myocardial infarction. Atherosclerosis (2003) 171:359–367.[CrossRef][Web of Science][Medline]
- Cesari M., Penninx B.W., Newman A.B., et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation (2003) 108:2317–2322.
[Abstract/Free Full Text] - Kloner R.A., Jennings R.B. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: Part 2. Circulation (2001) 104:3158–3167.
[Abstract/Free Full Text] - Lambiase PD, Edwards RJ, Cusack MR, et al. Exercise-induced ischemia initiates the second window of protection in humans independent of collateral recruitment. J. Am. Coll. Cardiol. (2003) 41:1174–1182.
[Abstract/Free Full Text] - Crisafulli A, Melis F, Tocco F, et al. Exercise-induced and nitroglycerin-induced myocardial preconditioning improves hemodynamics in patients with angina. Am. J. Physiol. Heart Circ. Physiol. (2004) 287:H235–H242.
[Abstract/Free Full Text] - Pedersen B.K., Steensberg A., Schjerling P. Muscle-derived interleukin-6: possible biological effects. J. Physiol. (2001) 536:329–337.
[Abstract/Free Full Text] - Kapadia S.R., Oral H., Lee J., et al. Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ. Res. (1997) 81:187–195.
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