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EDITORIAL

Induction of Heat Shock Protein 70 and Preconditioning by Sevoflurane: A Potent Protective Interaction Against Myocardial Ischemia-Reperfusion Injury

From the Anesthesia Service, the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin.

Address correspondence and reprint requests to Paul S. Pagel, MD, PhD, Clement J. Zablocki Veterans Affairs Medical Center, Anesthesia Service, 5000 W. National Ave, Milwaukee, WI 53295. Address e-mail to pspagel{at}mcw.edu.

Ritossa’s discovery that chromosomal "puffs" occur shortly after Drosophila salivary gland cells are exposed to hyperthermia, provided the first direct evidence of an acute genetic response to stress.1 Since this fascinating observation, it has become very clear that highly conserved "heat shock" or "stress" proteins are synthesized as a consequence of a variety of forms of tissue injury (e.g., hyperthermia, ischemia, inflammation, viral infection, toxin exposure) and play essential roles in cell survival.2 Heat shock proteins (HSP) are constitutively expressed and are quite abundant in the cytosol, endoplasmic reticulum, and mitochondria, even in the absence of physiologic stress.3 These proteins act as molecular chaperones that aid proper folding of other proteins, assist in multimeric protein complex assembly, maintain the structural integrity of steroid receptor proteins, and facilitate translocation of proteins within the cell and through its membranes.3 In the presence of cellular stress, HSP expression is enhanced, and this response serves to re-establish homeostasis by restoring denatured protein structure and facilitating metabolism of damaged proteins that are not amenable to repair.4,5 Several members of the HSP family also preserve mitochondrial function and cellular integrity during and after stress by inhibiting programmed cell death (apoptosis).4 Notably, induction of HSP by a stressful stimulus transiently protects the cell from damage by a subsequent and potentially lethal insult of similar or differing origin or intensity.2 Such a "delayed preconditioning-like" action may be especially beneficial in protecting normal cells from repetitive physiologic stress but, conversely, may also enhance the resistance of cancer cells to the cytotoxic effects of chemotherapeutic drugs or irradiation. Thus, the function, regulation, and mechanisms of action of HSP remain the subjects of considerable interest.

HSP are classified on the basis of molecular weight, among which the 70 kDa moiety (Hsp70) is one of the most plentiful and extensively studied.6 Hsp70 has been strongly implicated in cardioprotection against reversible and irreversible ischemic injury. Brief global or regional myocardial ischemia caused induction of Hsp70 in isolated rat7 or intact canine hearts,8 respectively, and this increase in Hsp70 was shown to protect myocardium against another ischemic episode.9 Induction of Hsp70 by hyperthermia,10 vasoactive drugs,11 or ethanol12 also produced cardioprotection against subsequent damage by prolonged ischemia. These data indicated that the cardioprotective effects of Hsp70 occur independent of the specific stress by which transcription and translation are initiated. Repetitive, brief episodes of coronary artery occlusion conducted 24 h before prolonged ischemia increased intracellular Hsp70 concentration concomitant with reductions in myocardial infarct size.13 The degree of cardioprotection correlated directly with the quantity of Hsp70 produced by the preceding stress event.14 Induction of Hsp70 by transient hyperthermia enhanced the functional recovery of postischemic-reperfused ("stunned") myocardium,15 and a sustained increase in Hsp70 mRNA was also observed in hibernating myocardium.16 Gene transfection of Hsp70 limited infarct size and preserved left ventricular contractile function after prolonged ischemia.17–19 Over-expression of Hsp70 in transgenic mice mitigated the extent of myocardial necrosis after prolonged ischemia in vivo.20 The viability of mitochondria isolated from transgenic mice over-expressing Hsp70 was enhanced after hypoxia-reoxygenation compared with mitochondria obtained from wild type mice.21 Induction of Hsp70 has also been suggested to play a role in cardioprotection in patients undergoing coronary artery bypass graft surgery.22

Geranylgeranylacetone (GGA) is an acyclic polyisoprenoid antiulcer drug that is a potent inducer of Hsp70. Exposure to GGA was initially shown to protect gastric mucosa23 and hepatocytes24 from damage caused by physical stress, hydrogen peroxide, or ethanol. A single oral dose of GGA administered 24 h before global ischemia increased Hsp72 (a member of the Hsp70 protein family) expression, improved left ventricular functional recovery, and reduced creatine kinase release in isolated rat hearts,25 activating the isoform of protein kinase C (PKC).26 More recently, mitochondrial K_ATP channels were also implicated in GGA-induced cardioprotection.27 In the current issue of Anesthesia & Analgesia, Kitahata et al.28 extend these previous findings25,27 by demonstrating that administration of GGA 24 h before prolonged coronary artery occlusion and reperfusion enhances Hsp70 expression and reduces myocardial infarct size in xylazine/ketamine-anesthetized, acutely instrumented rabbits.28 Pretreatment with the selective mitochondrial K_ATP channel antagonist 5-hydroxydecanoate abolished cardioprotection by GGA, suggesting that this channel is an important end-effector by which Hsp70 limits injury. The results with GGA were nearly identical to those obtained in rabbits exposed to transient systemic hyperthermia (42°C for 15 min), and provided further evidence that GGA produces cardioprotection by acting as a relatively selective pharmacological inducer of Hsp70.

The findings with GGA are very interesting when considered alone, but it is the authors’ examination of the interaction between induction of Hsp70 by GGA and preconditioning by sevoflurane that truly breaks new ground. Anesthetic preconditioning has been extensively studied for over a decade, but the ability of HSP to favorably modulate this phenomenon have been largely unexplored. Whereas 0.5 minimum alveolar concentration sevoflurane alone (administered for 30 min and then discontinued for 30 min before prolonged coronary artery occlusion, thereby providing the requisite "memory" period) failed to provide cardioprotection, administration of this concentration of the volatile anesthetic to rabbits pretreated with GGA markedly reduced myocardial infarct size to a significantly greater extent than observed with GGA alone (23 ± 17 versus 39% ± 10% of the left ventricular area at risk, respectively; P < 0.05). These findings demonstrate for the first time that induction of Hsp70 by GGA 24 h before prolonged ischemia and reperfusion lowers the threshold of sevoflurane preconditioning in vivo. Unfortunately, the authors did not probe the mechanism(s) for these novel findings nor did they examine the interactions of other HSP with anesthetic preconditioning. Nevertheless, several potential explanations for the current results may be entertained. Sevoflurane preconditioning alone did not affect Hsp70 expression, and GGA pretreatment caused similar increases in Hsp70 expression in the absence or presence of exposure to the volatile anesthetic. Isoflurane preconditioning was previously shown to reduce expression of Hsp70 detected using a microarray gene chip analysis in rat myocardium.29 Hsp70 expression was also unaffected 24 h after isoflurane preconditioning in a neonatal rat model of hypoxic-ischemic brain injury.30 Thus, it appears unlikely that administration of volatile anesthetics shortly before a prolonged ischemic episode provides protection against irreversible myocardial or neural injury by acutely enhancing Hsp70 transcription and translation. Notably, upregulation of lower molecular weight HSP were associated with isoflurane preconditioning,29 and important roles for Hsp27 (a key mediator of cytoskeletal integrity) and its upstream regulatory protein p38 mitogen-activated protein kinase, have been reported in cardioprotection produced by this volatile anesthetic and the anesthetic noble gas xenon.32 Thus, some evidence suggests that smaller HSP may be involved in anesthetic preconditioning, but the current results28 are the first to describe a fundamental cardioprotective interaction between induction of Hsp70 and anesthetic preconditioning.

The current28 and previous26,27 investigations provide pharmacological evidence that Hsp70-induced cardioprotection against ischemic injury is mediated by activation of PKC and opening of mitochondrial K_ATP channels. Central roles for PKC (primarily the , but also the isoform) and mitochondrial K_ATP channels have also been repeatedly demonstrated in anesthetic preconditioning.33,34 Thus, it is plausible to theorize that Hsp70 enhances the beneficial actions of sevoflurane preconditioning by simultaneous activation of these essential components of cardioprotective signal transduction. Reperfusion after prolonged ischemia initiates or accelerates apoptosis35 which, along with necrosis, determines the extent of myocardial infarction. Hsp70 has been shown to be an essential regulator of apoptosis.4,5 Hsp70 directly binds to apoptotic protease activation factor-1 (Apaf-1).36,37 This action effectively blocks the interaction of Apaf-1 and procaspase-9, thereby inhibiting the formation of the caspase-9 activation complex (also known as the apoptosome) and preventing activation of the caspase-dependent apoptosis cascade.4 Hsp70 also inhibits caspase-independent apoptosis through its interactions with apoptosis inducing factor and c-Jun N-terminal kinase.3,4 Volatile anesthetics also selectively inhibit many components of the cell suicide program, most notably, those regulated by the prosurvival signaling kinase cascade,38 and these actions contribute to cardioprotection after prolonged ischemia and reperfusion.39 For example, the phosphotidylinositol-3-kinase (PI3K)-Akt signaling cascade was shown to mediate isoflurane preconditioning, in part, by favorably affecting the balance between pro- and antiapoptotic proteins.40 Isoflurane also attenuated hypoxia-reoxygenation injury in vitro by activating PI3K-Akt and upregulating the crucial antiapoptotic B-cell lymphoma-2 protein.31 Thus, it also appears highly likely that induction of Hsp70 by GGA lowers the threshold of sevoflurane preconditioning to protect against myocardial infarction through additive or synergistic antiapoptotic effects. Elucidating the precise mechanisms responsible for these intriguing and previously unknown cardioprotective interactions between induction of HSP and preconditioning by volatile anesthetics will most certainly be important goals of future research.

	Footnotes

 
Accepted for publication April 24, 2008.

Supported by departmental funds.

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