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(Circulation. 1997;96:2311-2316.)
© 1997 American Heart Association, Inc.
Articles |
Delayed Coronary Endothelial Protection 24 Hours After Preconditioning
Role of Free Radicals
From the Department of Pharmacology, Vacomed, IFRMP 23, Rouen University School of Medicine and Rouen Hospital, France.
Correspondence to V. Richard, PhD, Service de Pharmacologie, Hôpital de Bois Guillaume, CHU de Rouen, 76031 Rouen Cedex, France. E-mail vincent.richard{at}chu-rouen.fr
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Abstract |
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Background Preconditioning (PC) induces delayed protection against myocardial ischemia/reperfusion (I/R) injury. Whether a similar late protective effect exists in coronary endothelial cells is not known. Thus, we assessed whether PC also induces late protection against endothelial injury after I/R and the potential role of reactive oxygen species as triggers for late PC in this setting.
Methods and Results Rats were subjected to sham surgery or to PC with 1 cycle of 2 minutes I/5 minutes R and 2 cycles of 5 minutes I/5 minutes R in the absence or presence of the free radical scavenger N-2-mercaptopropionyl glycine (MPG). Twenty-four hours later, rats were subjected to 20 minutes I/60 minutes R in the absence or presence of MPG. At the end of R, coronary segments (diameter, 200 to 300 µm) were removed distal to the site of occlusion and mounted in wire myographs. I/R reduced the relaxations to acetylcholine (maximal relaxations: sham, 72±6%; I/R, 31±6%), and this impairment was prevented by MPG (64±7%). PC improved the response to acetylcholine (48±6%), but this beneficial effect was abolished by MPG (23±5%).
Conclusions PC induces late protection against reperfusion-induced coronary endothelial injury. Moreover, in addition to being mediators of endothelial injury during reperfusion after prolonged ischemia, reactive oxygen species produced during PC also protect the coronary endothelium from reperfusion injury 24 hours later.
Key Words: endothelium • ischemia • infarction • arteries • vasodilation
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Introduction |
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Although preconditioning1 with brief periods of intermittent ischemia induces potent anti-ischemic effects, it is clear that this protection is short-lasting. Indeed, the protective effect is lost if the time interval between the preconditioning stimulus and the more prolonged period of ischemia is increased from several minutes to
2 to 3 hours.2 Recent evidence,
however, suggests that myocardial protection may reappear several hours
after preconditioning. Indeed, preconditioning performed 24 hours
before a sustained episode of coronary occlusion is associated
with a significant limitation of infarct size in dogs3 or
in rabbits,4 5 6 although a similar beneficial effect was
not found in another rabbit study.7 Moreover, such a
delayed (or late) protective effect by preconditioning extends to other
aspects of I/R injury, such as myocardial stunning.8 9
Although the mechanisms responsible for the late preconditioning
phenomenon are not elucidated, experimental evidence suggests that it
could be mediated by the expression of such protective proteins as
antioxidant enzymes10 or heat shock
proteins.4 11 12 In addition to damaging myocardial cells, I/R may be deleterious to the vasculature and especially to coronary endothelial cells.13 14 Specifically, the capacity of endothelial cells to release NO is affected by short-term15 16 17 18 or long-term19 20 reperfusion. Given the important role of NO as a vasodilator but also as a modulator of platelet function21 and leukocyte adhesion,22 23 such an impaired release of NO after reperfusion may indeed have important adverse effects on the coronary vasculature.
We have shown previously that "classic" preconditioning could prevent coronary endothelial injury after short-term17 or long-term20 reperfusion in rats. Preconditioning also improved endothelial function of dog coronary resistance arteries in vivo.24 However, whether preconditioning also induces delayed protective effects against endothelial injury is not known. Thus, the main goal of the present study was to assess whether preconditioning induces late protection against reperfusion-induced endothelial dysfunction in rats.
In addition, recent experiments performed in a pig model of myocardial stunning showed that administration of free scavengers during preconditioning both improved myocardial stunning and blocked the development of late preconditioning against further stunning.9 This raised the intriguing possibility that free radicals could be both responsible for myocardial dysfunction and mediators of subsequent preconditioning.9 A role for free radicals as triggers for late preconditioning has also been demonstrated in isolated myocytes.25 Thus, another goal of our study was to assess the potential role of reactive oxygen species as triggers of the late protective effects of preconditioning against endothelial injury.
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Methods |
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Experimental Preparation
Experiments were performed in male Wistar rats (Charles River, Saint Aubin les Elbeuf, France) weighing between 300 and 400 g, which were assigned to seven experimental groups (Fig 1
).
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On day 1, rats were anesthetized with 50 mg/kg IP of the short-acting anesthetic sodium methohexital. The animals were intubated with a small metal cannula and mechanically ventilated with room air supplemented with low-flow oxygen by use of a small-rodent ventilator (Apelex) at a rate of 60 cycles/min and a tidal volume of 1 mL/100 g body wt. Body temperature was maintained at 37°C with a thermostatted heating blanket connected to a rectal thermometer. A left thoracotomy was performed and the heart exposed. A 6-0 polypropylene suture was passed around the proximal left coronary artery, and the ends were passed through a small plastic tube to form a snare. Rats from the sham (day 1) groups (groups 1 through 5) were subjected to sham ischemia, whereas rats from the preconditioning groups (groups 6 and 7) were subjected to one cycle of 2 minutes of ischemia and 5 minutes of reperfusion followed by two cycles of 5 minutes of ischemia separated by 5 minutes of reperfusion. The rationale for performing an initial 2-minute period of occlusion was that reperfusion after such brief ischemia was not associated with severe arrhythmias (unlike what occurs after 5 minutes of ischemia) but was able to prevent the development of reperfusion arrhythmias after subsequent 5-minute periods of occlusion.
Animals from groups 2 (sham+free-radical scavenger) and 7 (preconditioning+free-radical scavenger) were treated with a continuous intravenous infusion (jugular vein) of MPG, a scavenger of oxygen-derived free radicals9 26 27 28 and especially of hydrogen peroxide29 (20 mg · kg-1 · h-1 starting 10 minutes before ischemia and ending 60 minutes after preconditioning or sham ischemia).
After induction of preconditioning or sham ischemia, the occluder was removed while the coronary suture was left in place, and the chest was closed in three layers (ribs, muscles, and skin) with polyester sutures. A plastic catheter connected to a 5-mL syringe was placed in the chest before sewing and was used to remove air from the chest after closure. The animals were allowed to recover from anesthesia (usually within 30 minutes), after which they were returned to their cage for 24 hours.
Twenty-four hours after preconditioning or sham ischemia, rats were reanesthetized with methohexital, intubated, and mechanically ventilated. Body temperature was maintained at 37°C with a thermostatted heating blanket connected to a rectal thermometer. The chest was reopened, and myocardial ischemia was induced as described above by use of the suture previously left in place. Animals were subjected to 20 minutes of ischemia followed by 60 minutes of reperfusion.17 Sham animals (groups 1 through 3) were treated identically except that the artery was not occluded.
Animals from group 3 (sham with MPG) or 5 (I/R with MPG) were treated with a continuous intravenous infusion (jugular vein) of MPG (20 mg · kg-1 · h-1 starting 10 minutes before ischemia or sham surgery and continuing throughout I/R).
In Vitro Vascular Studies
Coronary endothelial dysfunction was
assessed as described previously.17 20 30 Briefly, at the
end of the experiment, the heart was removed and immediately placed in
cold, oxygenated Krebs buffer. The left (ischemic)
coronary artery was carefully dissected free under a
microscope, and a segment 1.5 to 2 mm long was taken distal to the
site of occlusion and mounted in a small-vessel myograph for isometric
tension recording (JP Trading). Care was taken during the
dissection procedure to avoid damage to the
endothelium. After mounting, the vessels were allowed
to equilibrate for 30 minutes and then were progressively stretched and
set to a normalized internal diameter (range, 200 to 300 µm at a
level of stretch corresponding to 100 mm Hg). The normalization
procedure was performed as described previously.17 31
Baseline tensions after stretching were between 3.1 and 5.0 mN. After
another 60-minute equilibration period, segments were exposed to
increasing concentrations of serotonin
(10-9 to 10-5
mol/L; Sigma), which is not associated in this rat
coronary preparation with the release of
endothelium-derived relaxing factors and thus induces
only direct smooth muscle contraction.32 Vessels were then
washed, and concentration-response curves to acetylcholine
(10-9 to 10-5
mol/L; Sigma) or the NO donor SIN-1
(10-8 to 10-4
mol/L; a gift from Laboratoires Hoechst, Paris, France) were
studied in each ring after precontraction by serotonin.
Data Analysis
All results are expressed as mean±SEM. In all in vitro
experiments, n refers to the number of animals from which the arteries
were taken. Contractions to serotonin are normalized to
vessel length and expressed in millinewtons per
millimeter17 ; contractions are also expressed as
percentage of the maximal response. Relaxations to acetylcholine or
SIN-1 are expressed as a percentage of the contractions. In addition,
the negative logarithm of either the IC50 (in the case of
relaxations) or EC50 (in the case of contractions) was
calculated from concentration-response curves after adjustment to a
sigmoidal curve by a curve-fitting software (Origin, MicroCal Software,
Inc), and the means±SEM of these values are presented.
Contractile or relaxing responses were compared by a one-way ANOVA
followed when ANOVA was significant by a Tukey test for multiple
comparisons. A value of P
.05 was considered statistically
significant.
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Results |
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Mortality and Exclusions
A total of 68 rats were used for these studies. One rat from group 6 had to be excluded because of respiratory problems. Four rats died of ventricular fibrillation during preconditioning (3 from group 6 and 1 from group 7), and 2 died during the night after surgery (1 from group 1 and 1 from group 7). In addition, 4 rats died of ventricular fibrillation during the 20-minute period of ischemia (2 from group 4 and 2 from group 5), and 1 rat from group 4 died of ventricular fibrillation during reperfusion after the 20-minute period of ischemia. Thus, 56 rats completed the in vivo protocol. However, 3 additional rats (2 from group 5 and 1 from group 7) had to be excluded from the vascular studies because of technical problems during the in vitro experiments. Thus, the reported results are based on isolated arteries obtained from a total of 53 animals. The final number of animals in each group is shown in the Table
.
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Normalized Vessel Diameters and Contractile Responses to
Serotonin
The normalized internal diameters in each group are shown in the
Table
. No significant differences were observed among groups.
The maximal contractile responses and the EC50 for
serotonin are shown in the Table, and the responses to
increasing concentrations of serotonin (expressed as a
percentage of the maximal response) are shown in Fig 2. No significant differences in maximal
contractile responses were observed between the different groups. There
was a large heterogeneity in the sensitivity of the
contractile responses to serotonin. Compared with the
untreated I/R group (group 4), MPG (group 5) induced a significant
(P<.05) increase in the EC50 for
serotonin and also significantly decreased the contractile
response to 3x10-6 mol/L
serotonin.
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Relaxing Responses to SIN-1
The relaxing responses induced by increasing concentrations of the
NO donor SIN-1 are shown in Fig 3, and the IC50s are shown in the Table. In all groups, SIN-1
induced concentration-dependent relaxations that reached 100% at high
concentrations. I/R, preconditioning, or MPG did not affect the
responses to the NO donor.
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Relaxing Responses to Acetylcholine
Sham-operated animals. In coronary arteries
isolated from untreated, sham-operated animals (group 1), acetylcholine
induced concentration-dependent relaxations that reached 72±6% at the
highest dose (n=7; Fig 4). These relaxing
responses were not affected by MPG given on day 1 (group 2: maximal
responses, 69±7%) or on day 2 (group 3: maximal responses,
65±2%).
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Effect of I/R without or with MPG. Compared with
sham-operated animals, the response to acetylcholine was markedly
reduced in arteries taken from animals subjected to I/R (group 4;
maximal response, 31±6%, n=10; P<.01; Fig 5). However, the impaired response to
acetylcholine after I/R was prevented by the free-radical scavenger
MPG. Indeed, the maximal responses to acetylcholine in arteries taken
from MPG-treated rats (group 5) was 64±7% (n=8; P<.01
versus ischemic/reperfused, not significant versus sham; Fig 5).
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Effect of preconditioning without or with MPG. The impaired
response to acetylcholine after I/R (group 4) was significantly
improved by preconditioning performed 24 hours before prolonged
ischemia (maximal response: I/R, 31±6%, n=10;
preconditioning, 48±6%, n=10; P<.05; Fig 6). However, the response obtained in
preconditioned arteries (group 6) was significantly lower than that
obtained in sham-operated animals (group 1; P<.05).
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The improvement of the response to acetylcholine by preconditioning was
abolished by MPG given throughout preconditioning (group 7); indeed,
the maximal response to acetylcholine in arteries taken from
MPG-treated, preconditioned rats was 23±6% (n=6; P<.05
versus preconditioning; not significant versus
ischemic/reperfused; Fig 6).
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Discussion |
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The major findings of our study performed in a rat model of myocardial I/R were that (1) I/R markedly decreased the response to acetylcholine, and this was prevented by the free-radical scavenger MPG; (2) preconditioning performed 24 hours before prolonged ischemia significantly improved the impaired response to acetylcholine, and this delayed protective effect induced by preconditioning was abolished by MPG. Thus, we demonstrate that preconditioning induces late protective effects against reperfusion-induced endothelial injury. Moreover, we also demonstrate that production of reactive oxygen species during preconditioning may trigger a protective response that renders the endothelial cells more resistant to subsequent reperfusion injury. A similar dual role has recently been reported in the case of myocardial stunning.9
I/R did not affect the responses to serotonin or to the NO donor SIN-1, suggesting that it did not affect the responsiveness of the coronary smooth muscle either in terms of contraction or relaxation. However, the response to serotonin in reperfused arteries was slightly reduced by MPG. This decrease cannot be attributed to direct inhibitory effects of MPG on contraction, because no similar effect was found in sham arteries. One possibility is that reactive oxygen species produced in reperfused arteries tend to increase smooth muscle contraction. Such an increase might not be visible in reperfused arteries (compared with nonischemic), possibly because of opposite inhibitory effects of I/R on contraction. It must also be noted that we found a rather high heterogeneity in the responses to serotonin in our preparations. Such a high heterogeneity had already been observed in our previous study.20 The reason for this high variability is not known.
The major result of our study is that preconditioning induced late protective effects against reperfusion-induced endothelial injury, as assessed by the improved response to acetylcholine. This prevention was not complete, because the response to acetylcholine in preconditioned arteries (48±6%) was significantly lower than that of the corresponding sham arteries (72±6%). In contrast, in the same model, classic preconditioning completely normalized the response to acetylcholine.17 Thus, it appears that the endothelial protective effects of late preconditioning are not as marked as those of classic preconditioning.
The present study was not designed to assess the mechanisms by which preconditioning induces delayed endothelial protection. However, on the basis of what we know about the mechanisms of late preconditioning against other aspects of I/R injury, one could hypothesize that this late protective effect is due to the preconditioning-induced expression of HSPs4 and/or antioxidants.10
A potential role for HSPs in delayed protection is suggested by the fact that the expression of HSPs can be induced by short periods of ischemia,4 7 33 34 35 36 37 38 and overexpression of HSP70 in transgenic mice renders the heart more resistant to I/R.11 12 Importantly, endothelial cells may also express HSPs,39 40 and recent experiments suggest that transfection of cultured endothelial cells with HSPs renders those cells more resistant to hypoxia.41 To date, however, no direct link between the delayed protective effects of preconditioning and the expression of HSPs has been demonstrated directly because of the absence of interventions that may inhibit the expression of HSPs after brief ischemia. Because of this, the exact role of HSPs in endothelial protection cannot be precisely determined.
Our results with MPG administered on day 2 suggest that reperfusion injury to the endothelium is mediated by reactive oxygen species. Thus, one attractive hypothesis to explain the endothelial protective effects of preconditioning is that it somehow limits the production of free radicals during reperfusion, for example by increasing the antioxidant defenses of the cell. Indeed, brief ischemia may increase the activity of antioxidant enzymes such as SOD, catalase, or glutathione peroxidase in isolated myocytes10 25 and in vivo,37 42 43 44 although such an effect was not found in a study in rabbits.45 Moreover, prevention of the increase in SOD activity by an antisense oligonucleotide corresponding to the initiation chain of SOD abolished the protective effect of late preconditioning against hypoxia in isolated myocytes.10 Thus, such an increase in antioxidant activity represents a likely mechanism by which preconditioning induces endothelial protection in our experiments.
Administration of the free-radical scavenger MPG abolished the endothelial protective effects of preconditioning. This is similar to what has already been demonstrated in a pig model of myocardial stunning9 or in isolated myocytes25 and suggests that oxidative stress induced by reperfusion after preconditioning is necessary for the development of the protective mechanisms leading to endothelial protection. Because, as mentioned above, the two classes of protein most likely responsible for late preconditioning appear to be HSPs and antioxidant enzymes, one could speculate that oxidative stress might be a trigger for the expression of these protective proteins. Indeed, oxidant stress can induce HSPs in the heart38 and in endothelial cells.39 40 Similarly, oxidative stress leads to a delayed increase in the activity of antioxidant enzymes such as SOD, catalase, and glutathione peroxidase in endothelial cells.39 Moreover, in isolated myocytes, treatment with SOD during preconditioning prevents the preconditioning-induced delayed increase in SOD activity and abolishes the protective effects of late preconditioning.25 Thus, one likely explanation for our results is that oxidative stress induced by preconditioning induces a delayed increase in antioxidant activity in myocytes and/or endothelial cells, and this in turn protects the endothelial cells against further, more severe oxidative stress during reperfusion after prolonged ischemia. However, another study performed in isolated cells showed that hydrogen peroxide may induce delayed protection against further oxidative stress in the absence of any increase in antioxidant enzymes.46 Thus, whether an increase in antioxidant enzymes does contribute to the delayed protective effects induced by an initial oxidative stress (as may occur with preconditioning) is not clear.
One intriguing aspect of our results is the fact that free radicals may have opposite effects when produced during preconditioning (ie, beneficial) or during prolonged I/R (ie, deleterious). In the present study, we have not tried to mimic this dual effect by administering exogenous free radical–generating systems either at day 1 or day 2. We believe that such experiments are difficult to perform in vivo, because it is virtually impossible to assess how the effects of those systems compare with those of free radicals produced endogenously during reperfusion both in terms of the amount of free radicals produced and the exact species produced by the generating systems compared with the species produced endogenously. However, it is possible that these opposite effects may be related to different amounts of free radicals produced during preconditioning and prolonged I/R (as shown in isolated myocytes).25 Another possible explanation is that production of free radicals during preconditioning (unlike that occurring after prolonged ischemia) is not accompanied by other aspects of the inflammatory reaction that could contribute to endothelial injury (for example, complement activation and expression of leukocyte adhesion molecules, leading to neutrophil adhesion to endothelial cells).
In conclusion, our experiments demonstrate that preconditioning induces late protective effects against endothelial injury after I/R in rats. Moreover, we also demonstrate that in addition to being mediators of endothelial injury during reperfusion after prolonged ischemia, reactive oxygen species produced during preconditioning protect the coronary endothelium from reperfusion injury 24 hours later. Further studies are required to identify the precise mechanisms responsible for these delayed endothelial protective effects.
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Selected Abbreviations and Acronyms |
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Received February 6, 1997; revision received April 23, 1997; accepted April 28, 1997.
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