| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Medicine, Emergency Resuscitation Center, University of Chicago, Chicago, Illinois 60637
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Reactive oxygen species (ROS) and nitric
oxide (NO) are implicated in induction of ischemic
preconditioning. However, the relationship between these
oxidant signals and opening of the mitochondrial ATP-dependent
potassium (KATP) channel during early preconditioning is
not fully understood. We observed preconditioning protection by
hypoxia, exogenous H2O2, or PKC activator PMA
in cardiomyocytes subjected to 1-h ischemia and 3-h
reperfusion. Protection was abolished by KATP channel
blocker 5-hydroxydecanoate (5-HD) in each case, indicating that these
triggers must act upstream from the KATP channel.
Inhibitors of NO synthase abolished protection in preconditioned cells,
suggesting that NO is also required for protection. DAF-2 fluorescence
(NO sensitive) increased during hypoxic triggering. This was amplified
by pinacidil and inhibited by 5-HD, indicating that NO is generated
subsequent to KATP channel activation. Exogenous NO during
the triggering phase conferred protection blocked by 5-HD. Exogenous NO
also restored protection abolished by 5-HD or
N
-nitro-L-arginine methyl ester
in preconditioned cells. Antioxidants given during pinacidil or NO
triggering abolished protection, confirming that ROS are generated by
KATP channel activation. Coadministration of
H2O2 and NO restored PMA-induced protection in
5-HD-treated cells, indicating that ROS and NO are required downstream
from the KATP channel. We conclude that ROS can trigger preconditioning by causing activation of the KATP channel,
which then induces generation of ROS and NO that are both required for preconditioning protection.
hydrogen peroxide; nitric oxide; ischemia; cardiomyocytes
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
PRECONDITIONING CONFERS PROTECTION against ischemia-reperfusion injury in the heart. After a brief triggering stimulus is applied, the "early window" of protection begins within minutes and lasts for several hours. The persistence of protection after removal of the trigger indicates that a signal transduction pathway has been activated. Numerous triggers of preconditioning have been identified, including brief hypoxia/ischemia, opioids, ACh, bradykinin, activators of PKC, and pharmacological agents that activate the mitochondrial ATP-dependent potassium (mitoKATP) channel (10, 13, 15, 16, 26, 39, 50). However, the signal transduction sequence activated by these triggers is not fully understood.
Reactive oxygen species (ROS) have been implicated as participants in the signaling pathway involved in preconditioning triggering (1, 2, 4, 23, 41). We previously reported (42, 50) that exogenous H2O2 induces preconditioning in cardiomyocytes and that mitochondrial ROS are involved in the triggering by hypoxia or by ACh administration. However, an interesting controversy has developed regarding the relationship between the mitoKATP channel activation and the ROS signal during triggering. On one hand, Pain et al. (31) and Forbes et al. (6) showed that activation of the mitoKATP channel elicits an increase in ROS generation that is required for preconditioning protection. Moreover, ROS generation during ACh triggering is abolished when the KATP channel is inhibited, indicating that ROS signaling occurs as a consequence of channel activation (50). On the other hand, KATP channel inhibitors given during hypoxic triggering abolished protection without attenuating the ROS signal (43). These findings suggest that oxidant signals may potentially participate at multiple steps during triggering by 1) contributing to the activation of the mitoKATP channel during hypoxic triggering and 2) being generated as a consequence of mitoKATP opening during all forms of triggering. In either case, although ROS appear to play a central role in the signaling associated with triggering, the relationship between the mitoKATP channel and ROS generation during the triggering of early preconditioning is not fully understood.
Reactive nitrogen species (RNS) have also been suggested to participate
in the intracellular signaling during preconditioning triggering
(19, 29, 34, 49). However, the requirement for RNS in the
triggering of preconditioning is controversial, as some groups find
evidence for the involvement of nitric oxide (NO) during the early
window of protection (21, 32) but others do not
(27). In cardiomyocytes, inhibition of NO synthase (NOS) with N-nitro-L-arginine methyl
ester (L-NAME) did not abolish the ROS signal during
hypoxic triggering (42), which suggests that NO is not
required for ROS generation during hypoxic triggering. However, NOS
inhibitors did abolish the ROS signal during ACh triggering, and they
abrogated its protective effects (16). Therefore, the role
of NO in early preconditioning is not fully clear, and the
relationships among RNS, ROS, and the KATP channel are not
fully understood.
To clarify these relationships during the triggering phase of early
preconditioning, this study evaluated their interactions in the context
of a model (Fig. 1) based on previous
work from other laboratories (for reviews, see Refs. 5,
9, 18, 22, 28,
30) and our own. The model proposes that ROS are required at two separate steps in the triggering process and that NO is required
for events occurring downstream from the KATP channel. According to this model, preconditioning triggering requires both ROS
and RNS. We propose that ROS are required both upstream and downstream
of mitoKATP channel activation, whereas NO generation occurs downstream from the KATP channel.
|
| |
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Cardiac culture preparation. Embryonic chick ventricular myocytes were prepared as described previously (44). Spontaneously contracting cells on coverslips were studied at days 3-5 in a flow-through chamber under controlled O2 and CO2 conditions on an inverted epifluorescence microscope (43). The chamber and perfusate were maintained at 37°C; the flow rate was continuous (0.5 ml/min). Medium consisted of a balanced salt solution (BSS) with PO2 of 100 mmHg, PCO2 of 40 mmHg, pH 7.4, K+ concentration ([K+]) of 4.0 meq/l, and 5.6 mM glucose. Simulated ischemia consisted of BSS without glucose, with 2-deoxyglucose (20 mM) to inhibit glycolysis and [K+] of 8.0 meq/l. This solution was bubbled with 80% N2-20% CO2 gas to produce PO2 of 7 mmHg, PCO2 of 144 mmHg, and pH 6.8. Hypoxic preconditioning medium consisted of BSS without glucose bubbled with 95% N2-5% CO2. Reperfusion was with normal medium with glucose.
Video fluorescent microscopy. Fluorescent images were captured with a 12-bit digital camera (Metamorph, Universal Imaging). Cell viability was quantified with Sytox Green (100 µM; Molecular Probes), an exclusion fluorescent dye, to signal the loss of plasma membrane integrity associated with the loss of viability. This probe is not toxic to live cells, permitting its addition to the perfusate throughout. At the end of the experiment, cells were permeabilized with digitonin (300 µM) to obtain a measure of 100% cell death. Cell death during the experiment was calculated as the percentage of cells exhibiting nuclear staining relative to the value after digitonin.
NO measurements. Endogenous NO production was assessed with the specific probe diaminofluorescein (DAF-2, 10 µM; Calbiochem; Ref. 14). After the cells are loaded with the diacetate form of the dye, covalent reaction with NO causes an increase in fluorescence. Fluorescence intensity was measured over time (excitation 480 nm, emission 520 nm) and expressed in arbitrary units.
Experimental design.
The sequence of experimental interventions is shown in Fig.
2. Cardiomyocytes
were subjected to 60 min of simulated ischemia, followed by 180 min of reperfusion. Preconditioning was triggered by hypoxia (10 min),
followed by 10 min of reoxygenation before ischemia-reperfusion. Alternatively, preconditioning was
triggered with H2O2 (15 µM), PMA (200 nM), or
pinacidil (10 µM) for 10 min in lieu of hypoxia. The following
compounds were added to the perfusate at different times:
L-NAME (200 µM), 5-hydroxydecanoate (5-HD, 500 µM),
Go-6976 (100 nM), ebselen (5 µM), 2-mercaptopropionyl glycine (2-MPG,
400 µM), trifluoperazine (50 µM). Exogenous NO was supplied from a
tank containing 1% NO-99% N2. This gas was added to the
O2-CO2-N2 mixture used to bubble
the perfusate, at a rate determined to achieve a final concentration of
200 nM of NO in the headspace gas. NO and NO2
concentrations were measured in the chamber every 10 min by
chemiluminescence (Bedfont Scientific). Levels of NO2
generated from NO and O2 remained <2 ppm.
|
Data analysis. Replicate experiments were performed on separate coverslips, with each representing an n value of 1. Data are expressed as means ± SE. Analysis of variance tests were performed, with P < 0.05 considered significant.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
As seen previously with this model (43), cell death
was minimal during ischemia but rose to 58.1 ± 2.9%
(n = 8) after 3-h reperfusion in nonpreconditioned
cells. Preconditioning conferred significant protection regardless of
whether the triggering stimulus was hypoxia (33.0 ± 2.2%,
n = 10; P < 0.0001), the
KATP channel agonist pinacidil (29.9 ± 2.0%,
n = 5; P < 0.0001), exogenous H2O2 (36.7 ± 3.5%, n = 6; P = 0.0005), or PMA (26.2 ± 1.3%,
n = 3; P = 0.0001) (Fig.
3).
|
Role of ROS and PKC in opening of mitoKATP channel during triggering. Hypoxic preconditioning requires ROS generation from the mitochondrial electron transport chain, and exogenous H2O2 given during normoxia also confers protection (42). If these ROS cause activation of the mitoKATP channel, then inhibitors of that channel should abrogate the protection they confer. In the present study, the mitoKATP channel inhibitor 5-HD given throughout the experiment abolished protection induced either by hypoxia (55.5 ± 1.4%, n = 4) or by exogenous H2O2 (64.9 ± 7.2%, n = 6), thereby confirming the requirement for KATP channel opening in these responses (Fig. 3A). Protection was also abrogated when 5-HD was administered only during baseline and triggering associated with hypoxic (57.3 ± 5.5%, n = 3) or exogenous H2O2 (54.0 ± 1.6%, n = 3) preconditioning. These findings implicate ROS in the signaling that occurs upstream of the mitoKATP channel during triggering (Fig. 1).
Previous investigators have proposed that PKC promotes activation of the KATP channel during triggering (17, 36, 39). In this study, cells preconditioned with the PKC activator PMA exhibited significant protection compared with nonpreconditioned cells. Addition of 5-HD throughout the study abolished this protection (Fig. 3A). Furthermore, PKC inhibition by Go-6976, a selective PKC inhibitor, blocked the protection conferred by H2O2 (P = 0.01; Fig. 3B) but did not block protection induced by pinacidil. These results are consistent with the proposed activation of PKC by ROS at a site upstream from the mitoKATP channel (Fig. 1).Role of NO in preconditioning triggering.
To clarify whether NO participates in the signaling during triggering,
L-NAME was given throughout the study to inhibit NO synthase. This compound abolished the protection conferred by hypoxic
preconditioning (52.7 ± 1.5% cell death, n = 5;
Fig. 4A), by pinacidil (54.5 ± 3.4%, n = 5; Fig.
4B), and by exogenous H2O2 (56.1 ± 1.0%, n = 3; not shown). Preliminary
studies showed that lower concentrations (50-100 µM) of
L-NAME did not abolish protection (data not shown).
When given only during baseline and triggering, L-NAME
also abolished protection by pinacidil (52.5 ± 1.6%,
n = 3) and by PMA (60.7 ± 2.2%,
n = 3). Protection was also abolished when NOS was
inhibited by the calmodulin inhibitor trifluoperazine given only during
baseline and triggering (52.7 ± 3.7%, n = 3). These findings are consistent with the proposed involvement of NO in
the signaling associated with multiple triggers, at a site that must
occur downstream from the opening of the KATP channel (Fig.
1).
|
|
Production of ROS and NO as consequence of mitoKATP
channel activation.
mitoKATP channel activation (6, 31) and NO
(27) have each been suggested to trigger preconditioning
through a free radical-mediated mechanism (31). To test
this, exogenous NO was administered to nonpreconditioned cells during
baseline and triggering. This conferred significant protection (Fig.
6A), which was abrogated by
the antioxidant 2-MPG. Protection by NO was also abolished when 5-HD
was given during baseline and triggering. This is consistent with the
ability of exogenous NO to activate the mitoKATP
channel (35).
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
This study examined the relationships among ROS, NO, PKC, and the mitoKATP channel during the triggering of preconditioning. Preconditioning by hypoxia, H2O2, or PMA conferred protection that was blocked by mitoKATP channel inhibition (Fig. 1). Therefore, the signals activated by these triggers must precede opening of the KATP channel. The data also reveal that NO is required during triggering, based on the observations that 1) hypoxia-, H2O2-, or PMA-induced protection was blocked by NOS inhibitors, 2) exogenous NO restored protection that had been abrogated by NOS inhibition, and 3) fluorescence of the NO-sensitive probe DAF-2 increased during triggering. The stimulation of NO production during triggering must have been a consequence of KATP channel activation because 1) inhibitors of that channel attenuated the DAF-2 response, 2) protection induced by pinacidil was abolished by NOS inhibition, 3) pinacidil was associated with an augmentation of DAF-2 fluorescence, and 4) exogenous NO restored protection that had been abolished by 5-HD treatment in preconditioned cells.
These conclusions are based on the assumption that the inhibitors used in the study were specific for their intended targets. Several pharmacological agents used in the study of ischemic preconditioning have been shown to act at nonspecific sites, which could confound interpretation of this study. For example, Hanley et al. (11) recently reported that 5-HD acts as a substrate for acyl-CoA synthetase, that pinacidil selectively inhibits NADH oxidation, and that diazoxide can inhibit succinate dehydrogenase. Although it is not clear how these nonspecific targets could explain the effects of these drugs on preconditioning protection, it is clear is that future confirmation of the findings of our study will require the use of more definitive tools.
ROS signaling upstream of KATP channel. We (42) and others (1, 2, 41) have found that oxidant signals contribute to hypoxia-induced preconditioning. The ROS signal during hypoxic triggering was abolished by complex III inhibitors, which implicates the mitochondria in the oxidant generation (42). ROS signals appear to contribute to the activation of the KATP channel during certain types of preconditioning. Recently it was shown that superoxide can activate reconstituted mitoKATP channels in a planar lipid bilayer (51). In our study, hypoxia- or H2O2-induced protection was abolished by 5-HD given either throughout the study or only during the triggering phase. However, KATP channel inhibition did not abolish the ROS signal during hypoxic triggering (42). Therefore, at least some of the oxidant signaling during hypoxic triggering does not require opening of the KATP channel (Fig. 1).
Requirement for ROS downstream from mitoKATP channel. Data also suggest that KATP channel opening causes ROS generation. Pain et al. (31) found that antioxidants blocked protection induced by diazoxide, whereas Forbes et al. (6) found direct evidence of ROS generation in response to that KATP channel opener. Our finding that antioxidants abolished pinacidil-induced protection is consistent with their conclusions. During ACh-induced preconditioning, Yao et al. (50) found that KATP channel inhibition abolished both protection and the oxidant signal during triggering, suggesting that ROS must have been generated downstream from that channel. In cells preconditioned with opioid agonists, 5-HD also abolished the ROS signals and protection during triggering (23). Therefore, preconditioning by KATP channel agonists or certain receptor-mediated triggers causes KATP channel opening and subsequent ROS signaling. Hence, with certain triggers ROS do not appear to be involved until after the KATP channel opens (Fig. 1).
Relationship between ROS and PKC activation. The targets of PKC during the induction of preconditioning are not known. The notion that oxidants precede PKC activation is consistent with the observation that ROS can activate PKC (8, 37). Moreover, PKC inhibitors block protection without altering the ROS signal during hypoxic triggering (43), indicating that PKC acts upstream from the KATP channel but downstream from hypoxia-activated mitochondrial ROS generation (Fig. 1). Protection by exogenous H2O2 was abolished by PKC inhibition, indicating that ROS can potentially trigger preconditioning by promoting the activation of PKC. However, PKC inhibition did not block protection by pinacidil, indicating that PKC must be acting upstream from the KATP channel. Furthermore, protection induced by PKC activation was abolished by 5-HD, indicating that protection by PKC required the opening of the KATP channel. Collectively these observations indicate that ROS signals generated during hypoxia or H2O2 triggering are proximal to PKC activation (40). Furthermore, PKC induces protection through a mechanism requiring KATP channel activation (Fig. 1).
Liu et al. (17) reported that PKC activation can potentiate the KATP current induced by pinacidil, and Sato et al. (36) demonstrated that PKC primes the KATP channel to open earlier and more intensively during prolonged ischemia. Wang et al. (45) showed that PKC downregulation renders the KATP channel ineffective, thereby augmenting ischemic injury. These findings are consistent with a model in which PKC and the KATP channel are interrelated, with PKC acting as a regulator of that channel (Fig. 1). It is possible that ROS generated in response to KATP channel opening could augment PKC activation, which in turn could feedback to facilitate or prolong channel activity. Our findings confirm the linkage between PKC and activation of the KATP channel and extend previous work by linking this pathway to the early ROS and RNS bursts produced by various triggering agents.Requirement for NO in early preconditioning. The role of NO in early preconditioning is controversial. In some studies, NOS inhibitors failed to abolish preconditioning-induced protection in rats (24, 46), rabbits (27, 47), and pigs (33). In the rat heart, Weselcouch et al. (46) found that protection was not blocked by L-NAME at 30 µM, yet Lochner et al. (19) were able to block protection with 50 µM. Nakano et al. (27) found that NO donors induced preconditioning in the rabbit heart but were unable to abolish protection with L-NAME at 100 µM. We found that L-NAME inhibited protection at 200 µM, but preliminary studies failed to show any effect at 50 or 100 µM. Thus dose-dependent effects of NOS inhibitors may explain, at least in part, the negative results observed in some previous reports.
Our data indicate that NO is generated during triggering, and the resulting signal is required for protection. Endothelial type NOS is constitutively expressed in cardiomyocytes (3, 25), and an isoform of NOS similar to the endothelial isoform is expressed in cardiac mitochondria (7, 20). This places a potential source of NO in close proximity to the mitoKATP channel. In conscious rabbits, Xuan et al. (48) observed a rapid activation of calcium-dependent NOS after repeated cycles of hypoxia were used to trigger late preconditioning. Early preconditioning can be induced by the same triggering protocol (12), raising the possibility that NO generation during preconditioning involves Ca2+/calmodulin-dependent NOS activation. Our finding that protection was abrogated when NOS was blocked with the calmodulin inhibitor trifluoperazine is consistent with that possibility.ROS and NO signals during triggering: relationship to mitoKATP channel. Our data suggest that KATP channel activation triggers NO production. First, pinacidil-induced protection was abolished by L-NAME, and protection was restored by exogenous NO during triggering. Second, hypoxia-simulated NO production was abolished by KATP channel inhibition and was amplified by KATP channel openers. These findings indicate that NO generation is regulated by the KATP channel (Fig. 1). In rabbits, Ockaili et al. (29) reported that diazoxide mimicked both early and delayed preconditioning and that L-NAME applied before the sustained ischemia blocked protection. Our conclusion that NO is a mediator of protection regulated by KATP channel activation is therefore consistent with their data.
Other studies show that exogenous NO facilitates KATP channel activation (35), which suggests that the channel can be a target of endogenous NO production. In our study, exogenous NO was protective and this effect was blocked by 5-HD, suggesting that NO protected by opening that channel (35). Activation of the mitoKATP channel also triggers ROS production (6, 31), so 5-HD may have blocked protection because it prevented the ROS generation normally triggered by mitoKATP opening. In support of this interpretation, we found that protection induced by pinacidil was reversed by the antioxidants 2-MPG and ebselen, confirming that ROS are required downstream from mitoKATP channel. Also, exogenous H2O2 given with NO conferred protection when the mitoKATP was blocked. Finally, the protective effect of exogenous NO was abolished by the antioxidant 2-MPG. Collectively these results indicate that exogenous NO can lead to opening of the mitoKATP channel. The opening of that channel then leads to the generation of ROS and NO, both of which are required for preconditioning. During hypoxic triggering, NO and ROS produced by mitoKATP channel opening could feedback on the channel itself, thereby prolonging its activation and facilitating the downstream effects, including the further generation of ROS and NO.Requirement for ROS and RNS downstream from mitoKATP channel. Further evidence supporting the need for both ROS and NO downstream from the KATP channel came from cells preconditioned with PMA. In these cells, 5-HD blocked protection but a small degree of preconditioning was restored when exogenous NO was also given (Fig. 6B). If PMA protects by activating the KATP channel via PKC, then 5-HD should abolish protection (Fig. 1). In that situation, exogenous NO should fail to restore significant protection because of the lack of a simultaneous ROS signal. However, when both H2O2 and exogenous NO were administered, full protection was restored because both the ROS and NO arms were present. By the same reasoning, in cells preconditioned with H2O2 or hypoxia and blocked with 5-HD, exogenous NO was able to restore protection because the triggers were able to supply the necessary ROS component of signaling (Fig. 4C). Therefore, exogenous H2O2 and NO given together confer protection even if the KATP channel is blocked, because these molecules appear to act downstream of the channel in the hypoxic preconditioning process. We conclude that preconditioning triggers such as hypoxia or exogenous H2O2 can induce protection by causing activation of the mitoKATP channel via oxidant signaling. Protection ensues when NO and additional ROS are generated as a result of KATP channel opening. Triggers such as PMA or pinacidil can trigger KATP opening without the need for ROS upstream from the channel. Once opened, the KATP channel stimulates downstream production of ROS and NO, both of which are required for protection. Scavenging of either the NO or ROS signals generated downstream from the KATP channel was sufficient to abolish protection.
Oxidant signaling during triggering versus oxidant stress at reperfusion. Our data implicate both NO and ROS in the redox signaling involved in the induction of preconditioning. We previously observed (43) a large burst of oxidative stress at the start of reperfusion. This burst was smaller in preconditioned cells, which showed an improvement in survival. This illustrates the paradoxical involvement of ROS and NO in ischemia-reperfusion injury, with small redox-dependent signals involved in the induction phase and large bursts of oxidant stress contributing to cell death during ischemia and reperfusion.
The mechanism responsible for protection in preconditioning is not known. We speculate that ROS and NO are protective because they inhibit the process of cell injury during ischemia that leads to the uncontrolled oxidant burst generated at reperfusion. Although some protection is achieved if an antioxidant cocktail is administered only during reperfusion (43), the full significance of the oxidant burst at reperfusion is not clear. Although the burst is attenuated in preconditioned cells, it is not known whether the burst represents the cause of cell death or whether it is merely a marker of irreversible injury. To the extent that cell death in this model occurs through an apoptotic pathway, it is possible that NO and ROS signals act to inhibit the release of apoptosis-inducing proteins from the intermembrane space of mitochondria or that they inhibit the activation of caspases. In either case, the degree of protection appears to be greater in the intact heart, where 60-80% reduction in cell death can be achieved with preconditioning compared with the 40-50% seen in our cardiomyocyte model. Regardless of the model used, future progress in revealing the mechanisms of preconditioning protection will require a clearer understanding of the sequence of events that commit cells to a death pathway in ischemia and reperfusion.| |
ACKNOWLEDGEMENTS |
|---|
G. Lebuffe was supported by the French Lavoisier Program, the European Society of Intensive Care Medicine, a Schering Grant to the University of Lille, France, and a Philippe Foundation grant.
| |
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: P. Schumacker, Dept of Medicine, MC6026, Univ. of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637 (E-mail: pschumac{at}medicine.bsd.uchicago.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published September 26, 2002;10.1152/ajpheart.00706.2002
Received 9 August 2002; accepted in final form 18 September 2002.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Ambrosio, G,
Tritto I,
and
Chiariello M.
The role of oxygen free radicals in preconditioning.
J Mol Cell Cardiol
27:
1035-1039,
1995[Web of Science][Medline].
2.
Baines, CP,
Goto M,
and
Downey JM.
Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium.
J Mol Cell Cardiol
29:
207-216,
1997[Web of Science][Medline].
3.
Brahmajothi, MV,
and
Campbell DL.
Heterogeneous basal expression of nitric oxide synthase and superoxide dismutase isoforms in mammalian heart: implications for mechanisms governing indirect and direct nitric oxide-related effects.
Circ Res
85:
575-587,
1999
4.
Chen, W,
Gabel S,
Steenbergen C,
and
Murphy E.
A redox-based mechanism for cardioprotection induced by ischemic preconditioning in perfused rat heart.
Circ Res
77:
424-429,
1995
5.
Das, DK,
Engelman RM,
and
Maulik N.
Oxygen free radical signaling in ischemic preconditioning.
Ann NY Acad Sci
874:
49-65,
1999[Web of Science][Medline].
6.
Forbes, RA,
Steenbergen C,
and
Murphy E.
Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism.
Circ Res
88:
802-809,
2001
7.
Giulivi, C,
Poderoso JJ,
and
Boveris A.
Production of nitric oxide by mitochondria.
J Biol Chem
273:
11038-11043,
1998
8.
Gopalakrishna, R,
and
Anderson WB.
Ca2+- and phospholipid-independent activation of protein kinase C by selective oxidation modification of the regulatory domain.
Proc Natl Acad Sci USA
86:
6558-6762,
1989.
9.
Gross, GJ,
and
Auchampach JA.
Role of ATP dependent potassium channels in myocardial ischaemia.
Cardiovasc Res
26:
1011-1016,
1992
10.
Gross, GJ,
and
Fryer RM.
Sarcolemmal versus mitochondrial ATP-sensitive K+ channels and myocardial preconditioning.
Circ Res
84:
973-979,
1999
11.
Hanley, PJ,
Mickel M,
Loffler M,
Brandt U,
and
Daut J.
KATP channel-independent targets of diazoxide and 5-hydroxydecanoate in the heart.
J Physiol
542:
735-741,
2002
12.
Hill, M,
Takano H,
Tang XL,
Kodani E,
Shirk G,
and
Bolli R.
Nitroglycerin induces late preconditioning against myocardial infarction in conscious rabbits despite development of nitrate tolerance.
Circulation
104:
694-699,
2001
13.
Huh, J,
Gross GJ,
Nagase H,
and
Liang BT.
Protection of cardiac myocytes via 
1-opioid receptors, protein kinase C, and mitochondrial KATP channels.
Am J Physiol Heart Circ Physiol
280:
H377-H383,
2001
14.
Kojima, H,
Nakatsubo N,
Kikuchi K,
Kawahara S,
Kirino Y,
Nagoshi H,
Hirata Y,
and
Nagano T.
Detection and imaging of nitric oxide with novel fluorescent indicators: diaminofluoresceins.
Anal Chem
70:
2446-2453,
1998[Medline].
15.
Liang, BT,
and
Gross GJ.
Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels.
Circ Res
84:
1396-1400,
1999
16.
Liu, H,
McPherson BC,
Zhu X,
Da Costa ML,
Jeevanandam V,
and
Yao Z.
Role of nitric oxide and protein kinase C in ACh-induced cardioprotection.
Am J Physiol Heart Circ Physiol
281:
H191-H197,
2001
17.
Liu, Y,
Gao WD,
O'Rourke B,
and
Marban E.
Synergistic modulation of ATP-sensitive K+ currents by protein kinase C and adenosine. Implications for ischemic preconditioning.
Circ Res
78:
443-454,
1996
18.
Liu, Y,
Sato T,
Seharaseyon J,
Szewczyk A,
O'Rourke B,
and
Marban E.
Mitochondrial ATP-dependent potassium channels. Viable candidate effectors of ischemic preconditioning.
Ann NY Acad Sci
874:
27-37,
1999[Web of Science][Medline].
19.
Lochner, A,
Marais E,
Genade S,
and
Moolman JA.
Nitric oxide: a trigger for classic preconditioning?
Am J Physiol Heart Circ Physiol
279:
H2752-H2765,
2000
20.
Lopez-Figueroa, MO,
Caamano C,
Morano MI,
Ronn LC,
Akil H,
and
Watson SJ.
Direct evidence of nitric oxide presence within mitochondria.
Biochem Biophys Res Commun
272:
129-133,
2000[Web of Science][Medline].
21.
Lu, HR,
Remeysen P,
and
De Clerck F.
Does the antiarrhythmic effect of ischemic preconditioning in rats involve the L-arginine nitric oxide pathway?
J Cardiovasc Pharmacol
25:
524-530,
1995[Web of Science][Medline].
22.
Marber, MS.
Ischemic preconditioning in isolated cells.
Circ Res
86:
926-931,
2000
23.
McPherson, BC,
and
Yao ZH.
Morphine mimics preconditioning via free radical signals and mitochondrial KATP channels in myocytes.
Circulation
103:
290-295,
2001
24.
McQuillan, LP,
Leung GK,
Marsden PA,
Kostyk SK,
and
Kourembanas S.
Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms.
Am J Physiol Heart Circ Physiol
267:
H1921-H1927,
1994
25.
Michel, T,
and
Feron O.
Nitric oxide synthases: which, where, how, and why?
J Clin Invest
100:
2146-2152,
1997[Web of Science][Medline].
26.
Mitchell, MB,
Meng X,
Ao L,
Brown JM,
Harken AH,
and
Banerjee A.
Preconditioning of isolated rat heart is mediated by protein kinase C.
Circ Res
76:
73-81,
1995
27.
Nakano, A,
Liu GS,
Heusch G,
Downey JM,
and
Cohen MV.
Exogenous nitric oxide can trigger a preconditioned state through a free radical mechanism, but endogenous nitric oxide is not a trigger of classical ischemic preconditioning.
J Mol Cell Cardiol
32:
1159-1167,
2000[Web of Science][Medline].
28.
O'Rourke, B.
Myocardial KATP channels in preconditioning.
Circ Res
87:
845-855,
2000
29.
Ockaili, R,
Emani VR,
Okubo S,
Brown M,
Krottapalli K,
and
Kukreja RC.
Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide.
Am J Physiol Heart Circ Physiol
277:
H2425-H2434,
1999
30.
Okubo, S,
Xi L,
Bernardo NL,
Yoshida K,
and
Kukreja RC.
Myocardial preconditioning: basic concepts and potential mechanisms.
Mol Cell Biochem
196:
3-12,
1999[Web of Science][Medline].
31.
Pain, T,
Yang XM,
Critz SD,
Yue Y,
Nakano A,
Liu GS,
Heusch G,
Cohen MV,
and
Downey JM.
Opening of mitochondrial KATP channels triggers the preconditioned state by generating free radicals.
Circ Res
87:
460-466,
2000
32.
Ping, PP,
Takano H,
Zhang J,
Tang XL,
Qiu YM,
Li RX,
Banerjee S,
Dawn B,
Balafonova Z,
and
Bolli R.
Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits
a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning.
Circ Res
84:
587-604,
1999
33.
Post, H,
Schulz R,
Behrends M,
Gres P,
Umschlag C,
and
Heusch G.
No involvement of endogenous nitric oxide in classical ischemic preconditioning in swine.
J Mol Cell Cardiol
32:
725-733,
2000[Web of Science][Medline].
34.
Rakhit, RD,
Edwards RJ,
Mockridge JW,
Baydoun AR,
Wyatt AW,
Mann GE,
and
Marber MS.
Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes.
Am J Physiol Heart Circ Physiol
278:
H1211-H1217,
2000
35.
Sasaki, N,
Sato T,
Ohler A,
O'Rourke B,
and
Marban E.
Activation of mitochondrial ATP-dependent potassium channels by nitric oxide.
Circulation
101:
439-445,
2000
36.
Sato, T,
O'Rourke B,
and
Marban E.
Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C.
Circ Res
83:
110-114,
1998
37.
Servitja, JM,
Masgrau R,
Pardo R,
Sarri E,
and
Picatoste F.
Effects of oxidative stress on phospholipid signaling in rat cultured astrocytes and brain slices.
J Neurochem
75:
788-794,
2000[Web of Science][Medline].
38.
Sies, H.
Ebselen, a selenoorganic compound as glutathione peroxidase mimic.
Free Radic Biol Med
14:
313-323,
1993[Web of Science][Medline].
39.
Takashi, E,
Wang Y,
and
Ashraf M.
Activation of mitochondrial KATP channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway.
Circ Res
85:
1146-1153,
1999
40.
Thannickal, VJ,
and
Fanburg BL.
Reactive oxygen species in cell signaling.
Am J Physiol Lung Cell Mol Physiol
279:
L1005-L1028,
2000
41.
Tritto, I,
D'Andrea D,
Eramo N,
Scognamiglio A,
DeSimone C,
Violante A,
Esposito A,
Chiariello M,
and
Ambrosio G.
Oxygen radicals can induce preconditioning in rabbit hearts.
Circ Res
80:
743-748,
1997
42.
Vanden Hoek, TL,
Becker LB,
Shao Z,
Li C,
and
Schumacker PT.
Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes.
J Biol Chem
273:
18092-18098,
1998
43.
Vanden Hoek, TL,
Becker LB,
Shao ZH,
Li CQ,
and
Schumacker PT.
Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion.
Circ Res
86:
541-548,
2000
44.
Vanden Hoek, TL,
Shao Z,
Li C,
Zak R,
Schumacker PT,
and
Becker LB.
Reperfusion injury in cardiac myocytes after simulated ischemia.
Am J Physiol Heart Circ Physiol
270:
H1334-H1341,
1996
45.
Wang, Y,
Takashi E,
Xu M,
Ayub A,
and
Ashraf M.
Downregulation of protein kinase C inhibits activation of mitochondrial KATP channels by diazoxide.
Circulation
104:
85-90,
2001
46.
Weselcouch, EO,
Baird AJ,
Sleph P,
and
Grover GJ.
Inhibition of nitric oxide synthesis does not affect ischemic preconditioning in isolated perfused rat hearts.
Am J Physiol Heart Circ Physiol
268:
H242-H249,
1995
47.
Woolfson, RG,
Patel VC,
Neild GH,
and
Yellon DM.
Inhibition of nitric oxide synthesis reduces infarct size by an adenosine-dependent mechanism.
Circulation
91:
1545-1551,
1995
48.
Xuan, YT,
Tang XL,
Qiu Y,
Banerjee S,
Takano H,
Han H,
and
Bolli R.
Biphasic response of cardiac NO synthase isoforms to ischemic preconditioning in conscious rabbits.
Am J Physiol Heart Circ Physiol
279:
H2360-H2371,
2000
49.
Yao, Z,
and
Gross GJ.
Role of nitric oxide, muscarinic receptors, and the ATP-sensitive K+ channel in mediating the effects of acetylcholine to mimic preconditioning in dogs.
Circ Res
73:
1193-1201,
1993
50.
Yao, Z,
Tong J,
Tan X,
Li C,
Shao Z,
Kim WC,
Vanden Hoek TL,
Becker LB,
Head CA,
and
Schumacker PT.
Role of reactive oxygen species in acetylcholine-induced preconditioning in cardiomyocytes.
Am J Physiol Heart Circ Physiol
277:
H2504-H2509,
1999
51.
Zhang, DX,
Chen YF,
Campbell WB,
Zou AP,
Gross GJ,
and
Li PL.
Characteristics and superoxide-induced activation of reconstituted myocardial mitochondrial ATP-sensitive potassium channels.
Circ Res
89:
1177-1183,
2001
This article has been cited by other articles:
|
|
 |
|
  K. E. Brack, V. H. Patel, R. Mantravardi, J. H. Coote, and G. A. Ng Direct evidence of nitric oxide release from neuronal nitric oxide synthase activation in the left ventricle as a result of cervical vagus nerve stimulation J. Physiol., June 15, 2009; 587(12): 3045 - 3054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yasuda, H. Kobayashi, M. Iwasa, I. Kawamura, S. Sumi, B. Narentuoya, T. Yamaki, H. Ushikoshi, K. Nishigaki, K. Nagashima, et al. Antidiabetic drug pioglitazone protects the heart via activation of PPAR-{gamma} receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1558 - H1565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Misfeldt, A. Fago, and H. Gesser Nitric oxide increases myocardial efficiency in the hypoxia-tolerant turtle Trachemys scripta J. Exp. Biol., April 1, 2009; 212(7): 954 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. McCully, D. B. Cowan, C. A. Pacak, I. K. Toumpoulis, H. Dayalan, and S. Levitsky Injection of isolated mitochondria during early reperfusion for cardioprotection Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H94 - H105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Dossumbekova, E. V. Berdyshev, I. Gorshkova, Z. Shao, C. Li, P. Long, A. Joshi, V. Natarajan, and T. L. Vanden Hoek Akt activates NOS3 and separately restores barrier integrity in H2O2-stressed human cardiac microvascular endothelium Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2417 - H2426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. T. Costa and K. D. Garlid Intramitochondrial signaling: interactions among mitoKATP, PKC{varepsilon}, ROS, and MPT Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H874 - H882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Pasdois, B. Beauvoit, L. Tariosse, B. Vinassa, S. Bonoron-Adele, and P. D. Santos Effect of diazoxide on flavoprotein oxidation and reactive oxygen species generation during ischemia-reperfusion: a study on Langendorff-perfused rat hearts using optic fibers Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2088 - H2097. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Riess, A. D. Costa, R. Carlson Jr, K. D. Garlid, A. Heinen, and D. F. Stowe Differential Increase of Mitochondrial Matrix Volume by Sevoflurane in Isolated Cardiac Mitochondria Anesth. Analg., April 1, 2008; 106(4): 1049 - 1055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-H. Shao, W.-T. Chang, K. C. Chan, K. R. Wojcik, C.-W. Hsu, C.-Q. Li, J. Li, T. Anderson, Y. Qin, L. B. Becker, et al. Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1995 - H2003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z.-Q. Zhao and J. Vinten-Johansen Postconditioning: Reduction of reperfusion-induced injury Cardiovasc Res, May 1, 2006; 70(2): 200 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Diaz and G. J. Wilson Studying ischemic preconditioning in isolated cardiomyocyte models Cardiovasc Res, May 1, 2006; 70(2): 286 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Mabanta, P. Valane, J. Borne, and M. D. Frame Initiation of remote microvascular preconditioning requires KATP channel activity Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H264 - H271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F. Stowe, M. Aldakkak, A. K. S. Camara, M. L. Riess, A. Heinen, S. G. Varadarajan, and M.-T. Jiang Cardiac mitochondrial preconditioning by Big Ca2+-sensitive K+ channel opening requires superoxide radical generation Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H434 - H440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. La Padula and L. E. Costa Effect of sustained hypobaric hypoxia during maturation and aging on rat myocardium. I. Mechanical activity J Appl Physiol, June 1, 2005; 98(6): 2363 - 2369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Willems, K. J. Ashton, and J. P. Headrick Adenosine-mediated cardioprotection in the aging myocardium Cardiovasc Res, May 1, 2005; 66(2): 245 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kimura, G.-X. Zhang, A. Nishiyama, T. Shokoji, L. Yao, Y.-Y. Fan, M. Rahman, T. Suzuki, H. Maeta, and Y. Abe Role of NAD(P)H Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Cardioprotection of Ischemic Reperfusion Injury by Angiotensin II Hypertension, May 1, 2005; 45(5): 860 - 866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sarre, N. Lange, P. Kucera, and E. Raddatz mitoKATP channel activation in the postanoxic developing heart protects E-C coupling via NO-, ROS-, and PKC-dependent pathways Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1611 - H1619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C. Blunt, Y. Chen, J. D. Potter, and P. A. Hofmann Modest actomyosin energy conservation increases myocardial postischemic function Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1088 - H1096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Riess, L. G. Kevin, J. McCormick, M. T. Jiang, S. S. Rhodes, and D. F. Stowe Anesthetic Preconditioning: The Role of Free Radicals in Sevoflurane-Induced Attenuation of Mitochondrial Electron Transport in Guinea Pig Isolated Hearts Anesth. Analg., January 1, 2005; 100(1): 46 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Browe and C. M. Baumgarten Angiotensin II (AT1) Receptors and NADPH Oxidase Regulate Cl- Current Elicited by {beta}1 Integrin Stretch in Rabbit Ventricular Myocytes J. Gen. Physiol., August 30, 2004; 124(3): 273 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Qin, X.-M. Yang, L. Cui, S. D. Critz, M. V. Cohen, N. C. Browner, T. M. Lincoln, and J. M. Downey Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H712 - H718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Xu, X. Ji, and P. G. Boysen Exogenous nitric oxide generates ROS and induces cardioprotection: involvement of PKG, mitochondrial KATP channels, and ERK Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1433 - H1440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B Becker New concepts in reactive oxygen species and cardiovascular reperfusion physiology Cardiovasc Res, February 15, 2004; 61(3): 461 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sato, I. Sakuma, and D. D. Gutterman Mechanism of dilation to reactive oxygen species in human coronary arterioles Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2345 - H2354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Tauskela, E. Brunette, R. Monette, T. Comas, and P. Morley Preconditioning of cortical neurons by oxygen-glucose deprivation: tolerance induction through abbreviated neurotoxic signaling Am J Physiol Cell Physiol, October 1, 2003; 285(4): C899 - C911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. da Silva, A. Sartori, E. Belisle, and A. J. Kowaltowski Ischemic preconditioning inhibits mitochondrial respiration, increases H2O2 release, and enhances K+ transport Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H154 - H162. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
