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1 The Hatter Institute for Cardiovascular Studies, University College London Hospital and Medical School, London WC1E 6DB; and 2 The Institute of Child Health, University College London, London WC1N 1EH, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Reperfusion of ischemic myocardium is essential for tissue salvage but paradoxically contributes to cell death. We hypothesized that activation of potential survival pathways such as p42/p44 MAPK may prevent lethal reperfusion injury. Urocortin is a peptide factor that affects the p42/p44 MAPK signaling pathway. Both isolated and in vivo rat heart models were used to examine the potential for urocortin to prevent reperfusion injury. Isolated rat hearts underwent 35-min regional ischemia and 2-h reperfusion, with urocortin perfused for 20 min from the onset of reperfusion. In the in vivo study, urocortin was administered as an intravenous bolus 3 min before reperfusion with a protocol of 25-min regional ischemia and 2-h reperfusion. Blockade of the p42/p44 MAPK pathway with the inhibitor PD-98059 was used in both models. Urocortin attenuated lethal reperfusion-induced injury both in vitro and in vivo via a p42/p44 MAPK-dependent mechanism. Furthermore, Western blot analysis demonstrated the ability of urocortin to directly upregulate this signaling pathway. In conclusion, we believe that the p42/p44 MAPK-dependent signaling pathway represents an important survival mechanism against reperfusion injury.
experimental; organ; molecular biology; ischemia; infarction
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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REPERFUSION IS THE ONLY MEANS of salvaging ischemic myocardium and limiting infarct development. However, it is paradoxically associated with cell death termed lethal reperfusion injury (12, 19, 28).
Proving the existence of lethal reperfusion injury is difficult, and the only way to investigate this phenomenon is by the administration of possible modulators of such injury immediately before reperfusion (but not before ischemia) with the subsequent assessment of infarct size. To date there is no experimental agent that has been shown to be effective in limiting lethal reperfusion injury both in animal models and the clinical setting. However, the clinical impact of such an intervention might be dramatic if it were used as an adjunct to thrombolysis at the time of reperfusion in the setting of acute myocardial infarction.
Recent studies suggest that p42/p44 MAPK and big MAPK (BMK1) (21,
22) are part of a "survival" pathway whereas p38
(specifically the p38
isoform) (17) and JNK mediate a
"death" pathway in the ischemic-reperfused myocardium
(2, 29). Yellon and Baxter (27) have
suggested that p42/p44 MAPK pathway may represent an important salvage
mechanism in the reperfused myocardium.
Urocortin (24) is a peptide related to the hypothalamic hormone corticotrophin-releasing factor (CRF) that was originally cloned from rat and thereafter the human brain and has receptors also expressed within peripheral tissues outside the central nervous system, including the heart (1, 10, 18). Urocortin has been shown to protect neonatal rat cardiomyocytes from cell death when administered before hypoxia or at the point of reoxygenation (3). Furthermore, urocortin has also been shown to induce p42/p44 MAPK phosphorylation in serum starved neonatal rat cardiomyocytes and inhibition of urocortin-mediated cardioprotection by the MEK1-p42/p44 MAPK-specific inhibitor PD-98059 suggests that this pathway may be important (3).
The aim of this study was to evaluate the infarct-limitation effects of urocortin when administered at reperfusion in adult rats both in isolated crystalloid-perfused hearts, and more importantly in an in vivo model of acute myocardial infarction. Furthermore, any possible infarct-altering hypotensive effects of urocortin in vivo (26) would be compared with a similar hypotensive effect caused by intermittent intravenous administration of nitrates at reperfusion. The role of p42/p44 MAPK in urocortin-induced cardioprotection was further evaluated both in the in vitro and in vivo setting to investigate the critical role for this MAPK in protecting against reperfusion injury. In addition, the specific effect of urocortin on p42/p44 MAPK phosphorylation and upregulation after ischemia-reperfusion was studied with the use of Western blot analysis.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The investigation conforms to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1996).
Isolated rat heart preparation.
After pentobarbital sodium (50 mg/kg ip) anesthesia was administered,
the hearts of 40 male Sprague-Dawley rats (280-350 g) were excised
and retrogradely perfused on a Langendorff apparatus (at 80 mmHg).
Temperature was maintained at 37 ± 0.5°C and a water-filled latex balloon was inserted into the left ventricle and inflated to set
end-diastolic pressure at 5-10 mmHg. Regional ischemia was
achieved by pulling on a snare passed around the main branch of the
left coronary artery and confirmed by a substantial fall in both left
ventricular developed pressure (LVDP) and coronary flow (CF). All
hearts underwent 15 min of stabilization, 35 min of regional
ischemia, and 2 h of reperfusion. Procedural exclusion criteria included a rate pressure product (RPP) <18,000
mmHg · beat
1 · min at the end of
the stabilization period, an inability to maintain >80% of initial
contractile function through the stabilization period, a CF <8 and
>16 ml · min1 · 100 g
tissue1 at the end of the stabilization, and persistent
arrhythmias throughout stabilization. Four groups were included in this
study (Fig. 1A). Control
hearts underwent 35 min of regional ischemia and 2 h of reperfusion. Further groups had urocortin (108 mol/l)
alone or both urocortin (108 mol/l) and PD-98059 (5 µmol/l) or PD-98059 (5 µmol/l) alone perfused for the first 20 min
of reperfusion starting 3 min before the onset of reperfusion.
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Experimental groups for phosphorylated p42/p44 MAPK assessment. Various experimental groups (n = 3-5 per group) were studied for analysis of phospho-p42/p44 MAPK using the isolated perfused rat heart. Sham hearts were used after a 60-min perfusion (stabilization). Control experiments followed the same protocol as the infarct studies: 35-min regional ischemia and 2-h reperfusion. Individual hearts were biopsied once from the cardiac apex after 32-min ischemia or after 35-min ischemia, followed by 5-, 10-, 20-, and 120-min reperfusion. Hearts perfused with urocortin at reperfusion after 35-min ischemia were biopsied after 5-, 10-, 20-, and 120-min reperfusion. The hearts treated with both urocortin and PD-98059 or PD-98059 alone were biopsied after 35-min ischemia and 10-min reperfusion. All drugs were perfused following the same protocols used for the in vitro infarct-based studies. At the end of each experiment the estimated risk zone at the apex of the heart was rapidly frozen in liquid nitrogen and used later for Western blot analysis of the phosphorylated form of p42/p44 MAPK with the use of a New England Biolab kit (following the manufacturer's instruction). The resulting autoradiography films were scanned on a flatbed picture/document scanner and the digital image saved to a disk. The image was imported into NIH Image software (version 1.61). The relative densitometry was determined using the grayscale technique with the use of the supplied "gel plotting macro." Images were calibrated against absolute densitometer values and results expressed as a mean densitometry arbitrary units ± SE.
In vivo model of ischemia-reperfusion in rats. After anesthesia with intraperitoneal pentobarbital sodium (50 mg/kg), 66 male Sprague-Dawley rats (330-380g) underwent an open-chest surgical procedure involving tracheotomy, positive pressure ventilation using room air supplemented with oxygen, right common carotid artery cannulation enabling constant blood pressure (BP) and heart rate (HR) monitoring as well as right jugular vein cannulation for the intravenous administration of drugs. After a left parasternal thoracotomy was performed, a 6-0 silk snare was placed around the left anterior descending coronary artery before undergoing 25 min of regional ischemia and 2 h of reperfusion. Intermittent arterial blood gas analysis was performed and ventilation was adjusted to maintain a physiological pH (7.35-7.45), PCO2, and PO2. HR and BP were measured at regular intervals throughout the experiments. Procedural exclusion criteria included blood loss of >1 ml during the operative procedure, poor temperature control with rectal temperature >38°C, bleeding from the epicardial surface on induction of ischemia, a mean arterial pressure <90 mmHg during stabilization, and metabolic acidemia with a pH <7.35. Six groups were included in this study (Fig. 1B). The control group underwent 25 min of regional ischemia and 2 h of reperfusion. Ischemia was confirmed by regional ischemic pallor, hypokinesia, and a fall in BP. The groups treated with either 1 or 15 µg/kg urocortin had the drug administered intravenously 3 min before reperfusion. The group treated with PD-98059 (4 mg/kg) had the inhibitor administered intravenously 6 min before reperfusion. The fifth group had both PD-98059 (4 mg/kg) administered intravenously 6 min before reperfusion and urocortin (15 µg/kg) administered intravenously 3 min before reperfusion. In the final group, glyceryl trinitrate (GTN) (0.04 mg/ml) was administered by slow intermittent intravenous infusion for the duration of reperfusion to mimic the hypotensive effects of urocortin. After 2 h of reperfusion, the heart was excised and Langendorff perfused briefly with saline to remove the blood.
Determination of infarct size. At the end of each experiment (after 2-h reperfusion), the silk suture was reoccluded and a 5% solution of Evans blue dye was infused into the perfusate to mark the risk zone as unstained (not blue) tissue. The hearts were then frozen and cut into 2-mm thick slices parallel to the atrioventricular groove. The slices were then thawed and incubated in a 1% triphenyltetrazolium chloride (TTC) phosphate-buffered solution at 37°C for 15 min and fixed in 10% formalin, to enhance the contrast of the Evans blue and TTC staining. Slices were then compressed by placing them between two glass plates separated by a 2 mm spacer. The area of the left ventricle (stained blue), the risk zone (stained red by TTC), and the infarcted area (unstained) were traced onto acetate transparencies, and with the use of computerized planimetry program (Summa Sketch II, Summa Graphics; Seymour, CT), the respective volumes were calculated. Infarct size was expressed as a percentage of the risk zone. All measurements were performed in a blinded fashion.
Statistical analysis.
Data from the experiments are expressed as means ± SE.
Differences between the means were compared using the Student's
t-test. The risk and infarct volumes were tested for group
differences by a one-way ANOVA. Comparisons of CF (normalized to the
heart weight and expressed as
ml · min1 · 100 g tissue1),
RPP (calculated from HR × LVDP), and BP were performed by
repeated measures of ANOVA. *P < 0.05 was considered significant.
Drugs and materials. Urocortin and PD-98059 were obtained from Sigma (Dorset, UK). Urocortin was initially dissolved in a 0.01% acetic acid solution and PD-98059 was dissolved in dimethyl sulfoxide (DMSO) with a final in vitro concentration of 0.02%. PD-98059 was injected intravenously, dissolved in 0.2 ml 99.5% DMSO solution, and the cannula was subsequently flushed with 0.09% saline. Neither vehicle had any inherent effect on infarct size. GTN (1 mg/ml) was obtained from Faulding (Leamington Spa, UK) and diluted to the final concentration in 0.09% saline.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Urocortin protects in vitro isolated perfused heart from
reperfusion injury via p42/p44 MAPK pathway.
Urocortin (108 M) perfused for the first 20 min of
reperfusion significantly reduced infarct size from 49.3 ± 2.2%
in control hearts to 22.7 ± 2.9% in urocortin-treated hearts
(P < 0.01) (Fig. 2). The
MEK1 inhibitor PD-98059 completely abrogated the protective effects of
urocortin with infarct sizes returning to 49.8 ± 4.3%. PD-98059
alone had no effect on infarct size compared with control (43.7 ± 1.8%).
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RPP, CF rate, and ischemic risk zone analysis for in vitro
experiments.
The RPP (Table 1) and CF rate (Table
2) analysis showed there to be no
significant difference between the groups at baseline (15-min
stabilization). The RPP decreased significantly during ischemia
in all groups, and there was only partial recovery during reperfusion.
Urocortin had no adverse effect on cardiac function. The CF rate
(expressed in ml · min1 · 100 g
tissue1) was similar at baseline and decreased to a
similar extent during regional ischemia. The ischemic
risk volumes (zones) were similar within each group.
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Effect of urocortin on p42/p44 MAPK phosphorylation.
After the in vitro infarct size experiments, it was important to
examine the effect of urocortin (and PD-98059) on p42/p44 MAPK
phosphorylation throughout the ischemia-reperfusion period (Figs. 3 and 4). In the control
experiments, p42/p44 MAPK phosphorylation was upregulated at all time
points measured compared with the stabilized preparation, with greatest
activation seen at 5-min reperfusion (Fig. 3). After the administration
of urocortin at reperfusion (Fig. 3), there was a significant
upregulation of the p42/p44 MAPK signaling pathway, with maximal
induction of phospho-p42/p44 MAPK occurring at 10-min reperfusion
compared with control values. Interestingly, at 20-min reperfusion, the level of phospho-p42/p44 MAPK in the urocortin-treated group was lower
than that at 10-min reperfusion despite the presence of urocortin,
although still significantly greater than its time-matched control. By
2-h reperfusion, there was no difference between the urocortin-treated
and control groups. In the groups treated with urocortin + PD-98059 or PD-98059 alone (Fig.
4), no significant difference was noted
in phospho-p42/p44 MAPK levels compared with their time-matched
controls (at 10-min reperfusion).
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Urocortin protects heart from reperfusion injury in anesthetized in
vivo adult rat via p42/p44-dependent signaling pathway.
To advance the clinical relevance of the study, we examined for the
first time the cardioprotective effect of urocortin using the in vivo
rat heart model. Urocortin administered just before reperfusion was
also seen to significantly reduce myocardial infarction in a
dose-dependent manner (Fig. 5). Infarct
size was reduced from 48.6 ± 2.6% in control hearts to 29.3 ± 2.7% in rats treated with 15 µg/kg urocortin (P
< 0.01). Rats treated with 1 µg/kg of urocortin at reperfusion
showed no reduction in infarct size (54.8 ± 4.5%) compared with
control hearts. When PD-98059 (4 mg/kg) was injected intravenously 3 min before urocortin (15 µg/kg), the infarct reduction was abolished
and infarct sizes were comparable to control hearts (47.0 ± 4.3 vs. 48.6 ± 2.6%). PD-98059 (4 mg/kg) alone had no effect on
infarct size compared with control hearts (55.4 ± 5.7 vs.
48.6 ± 2.6%).
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Mean arterial BP, HR, and arterial blood gas analysis for the in
vivo study.
Mean arterial pressure and HR measurements (Table
3) were recorded throughout the
ischemia-reperfusion protocol. Both urocortin at 1 and 15 µg/kg significantly reduced the mean arterial pressure (P < 0.05) compared with control after intravenous
infusion, and this reduction was maintained throughout the reperfusion
period. Only at 5- and 60-min reperfusion was the mean arterial
pressure of the group treated with urocortin 15 µg/kg significantly
less than that treated with urocortin 1 µg/kg (P < 0.05). In the urocortin 15 µg/kg-treated group, a significantly
higher HR was noted at 60 and 120 min of reperfusion. GTN was infused
intravenously at a variable rate (and not continuously) to mimic the
hypotensive effects of urocortin 15 µg/kg. No significant changes in
HR were noted in this group compared with control. DMSO, the vehicle in which PD-98059 was solubilized, caused a transient hypertensive effect
that normalized within 5 min. This had no effect on infarct size. The
arterial pH was maintained between 7.35 and 7.45 for the duration of
the experiments, and the PO2 was held between 25 and 35 kPa. The whole body and heart weights and the risk zones were
similar for all groups studied (Table 4).
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Hypotensive effect of GTN does not affect infarct size. To ascertain whether the hypotensive effect seen with urocortin could possibly account for the protection observed, we examined the effect of GTN used intermittently at a dose that mirrored the hypotension caused by 15 µg/kg urocortin at reperfusion. This hypotensive effect of GTN did not cause any reduction in infarct size (Fig. 5). The infarct size of the GTN-treated group was no different from that of control hearts (48.8 ± 4.2 vs. 48.6 ± 2.6%). Therefore, the specific cardioprotective of urocortin was unrelated to hypotension.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Reperfusion remains the only means of salvaging ischemic myocardium and limiting infarct development. The challenge of developing a reliable means of protecting the heart from reperfusion-induced injury must be met if we are to beneficially affect the survival of patients suffering from myocardial infarction. We show that urocortin, acting via a p42/p44 MAPK-dependent signaling pathway, is able to protect both the in vitro and in vivo rat heart from reperfusion injury possibly through direct upregulation of a reperfusion injury salvage kinase.
Although there are inherent limitations when in vitro systems attempt to simulate in vivo ischemia and reperfusion, cell-based studies have shown that simulated reperfusion (or reoxygenation) results not in the accelerated lysis of already dead cells, but rather in lethal injury to cells that were previously viable (25). The ischemic alterations of cellular conditions are however, necessary prerequisites and indeed set the stage for lethal reperfusion injury.
In neonatal cardiomyocytes, Brar et al. (3) showed that urocortin can significantly attenuate the injury of reoxygenation as measured using markers of both necrosis and apoptosis. This protection was shown to be independent of urocortin-induced p38 MAPK or JNK phosphorylation, and specific inhibition of p38 MAPK failed to inhibit the cardioprotective effect of urocortin (3). In this study, we have demonstrated in the intact heart (both in vitro and in vivo), the importance of urocortin acting via the p42/p44 MAPK in protecting the heart against infarct-related cardiac dysfunction. MAPKs are an important area of focus to elucidate the complex relationship between signal transduction and this balance of survival and death in the ischemic myocardium. The dynamic relationship of their activities may be important in determining the outcome of the cardiomyocyte after the stress of reperfusion. In our study, we have demonstrated the ability of urocortin to augment the phosphorylation of p42/p44 MAPK in the reperfused myocardium and suggest that it is possibly through this mechanism that the myocardium is protected from lethal reperfusion injury. However, it is possible that the increased level of infarction in control hearts directly reduced detectable levels of phospho p42/p44 MAPK in these tissues. It is also possible that the rapid decline in phospho-p42/p44 MAPK after 10-min reperfusion despite the presence of urocortin may be the result of MAPK phosphatase induction, which has previously been demonstrated to cause dephosphorylation and inactivation of p42/p44 MAPK (8). It should be emphasised that in our study the effect of PD-98059 was effective in both attenuating the protection (infarct size) obtained with urocortin at reperfusion and attenuating the phosphorylation and downregulation of the p42/p44 MAPK.
It is not fully understood how p42/p44 MAPK upregulation may protect the myocardium against the consequences of reperfusion injury. p42/p44 MAPK and BMK1 have been shown to protect against ischemia-reperfusion-induced cardiomyocyte cell death (21, 22). In addition to the above study, one could speculate that the p90 ribosomal S6 kinase may have special functions as a substrate of the p42/p44 MAPK (7), both by inhibiting components of the cell death machinery [e.g., phosphorylation and inhibition of Bcl-2 associated death promoter (BAD)] (23) and increasing transcription of prosurvival genes. p42/p44 MAPK acting downstream of B-Raf may also inhibit cytosolic caspase activation following release of cytochrome c from the mitochondria (6). Furthermore, protein kinase B (PKB) has been shown to inactivate caspase-9 through phosphorylation (4), though other serine-threonine kinases may also modify such caspase activation. It seems that p42/p44 MAPK and PKB (4) are both able to target BAD and inactivate its proapoptotic function through phosphorylation at two different sites (protein kinase A is able to inactivate BAD through a third phosphorylation site) (9). PKB has also been shown to maintain mitochondrial membrane integrity and prevent release of cytochrome c independent of BAD phosphorylation (14). This effect may be partly explained by the ability of PKB to activate mitochondrial Raf-1 and the downstream p42/p44 MAPK pathway (16). It should be noted that although we believe urocortin capable of protecting against apoptosis in the heart, our end point in the whole heart has been that of infarct size reduction.
In our study, the hemodynamic effects of urocortin in vivo appeared to play no role in the cardioprotection from reperfusion injury. Although a significant reduction in mean arterial pressure was found in the group treated with 1 µg/kg urocortin, no cardioprotective effect was seen. Hypotension during reperfusion has not been shown to limit infarct size. To examine this in more detail we used intravenous GTN intermittently during reperfusion to mimic the hemodynamic effect of 15 µg/kg urocortin as closely as possible. Although we were able to significantly reduce the mean arterial pressure comparable to 15 µg/kg urocortin, no reduction of infarct size was noted. Whereas GTN (and other nitrates) have been shown to protect the myocardium if administered before ischemia (11), these agents have not been shown to protect the heart from lethal reperfusion injury (when given at reperfusion). Furthermore, we saw no changes in cardiac function in the in vitro experiments, where urocortin maintained a powerful protective effect in a neutrophil free crystalloid buffer-perfused Langendorff system.
Studies (20) in chronically instrumented conscious sheep
have showed that urocortin induces a dose-dependent increase in HR,
cardiac output, mean arterial pressure, and CF rate (doses of between 1 and 100 µg injected intravenously). There was no change in peripheral
vascular conductance and stroke volume. All urocortin-induced
cardiovascular effects were inhibited by prior treatment with the CRF
antagonist -helical CRF. In contrast, however, when urocortin was
administered in freely moving rats it produced a pronounced and
prolonged reduction of mean arterial pressure (as demonstrated in our
anesthetized rats). Both the size and duration of this effect were dose
dependent (26). These disparate hemodynamic actions of
urocortin in the sheep and rat may be due to species-specific
differences in the binding of CRF and urocortin to peripheral CRF-R2.
Mice generated lacking expression of CRF-R2 have been shown to have
higher resting BPs, and in response to systemic urocortin fail to show
any enhanced cardiac performance or reduced BP (5).
In conclusion, we have shown for the first time that urocortin can protect the intact heart from reperfusion injury both in vitro and in vivo and that this protection appears to be associated with upregulation of a p42/p44 MAPK-dependent signaling pathway. Future studies will needed to investigate the importance of the p42/p44 MAPK pathways in mediating the protective effect of both urocortin as well as other potential therapies that may affect this signaling pathway. We believe the heart possesses prosurvival reperfusion injury salvage kinases pathways that may be exploited when developing agents that can be used to protect the myocardium against the consequences of lethal reperfusion injury.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. M. Yellon, The Hatter Institute for Cardiovascular Studies, Div. of Cardiology, Univ. College London Hospitals and Medical School, Grafton Way, London WC1E 6DB, UK (E-mail: hatter-institute{at}ucl.ac.uk).
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.
June 13, 2002;10.1152/ajpheart.01089.2001
Received 30 December 2001; accepted in final form 10 June 2002.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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