© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Second window of ischemic preconditioning regulates mitochondrial permeability transition pore by enhancing Bcl-2 expression
aDepartment of Surgery II, Kochi Medical School, Kohasu, Oko, Nankoku, Kochi, Japan
bDepartment of Endocrinology, Tokyo Medical and Dental University, Tokyo, Japan
* Corresponding author. Tel.: +81-88-880-2375; fax: +81-88-880-2376. sasaguri{at}kochi-ms.ac.jp
Received 1 November 2002; accepted 23 March 2003
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Objective: The second window of protection (SWOP) following brief coronary artery occlusion begins at 24 h and may last up to 72 h and occurs via many unknown mechanisms. We investigated the role of the mitochondrial permeability transition pore (PTP), a non specific pore in the inner membrane of the mitochondria in this phenomenon. Methods: Ischemic preconditioning (IP) was induced in Wistar rats by left coronary artery occlusion (four, 3-min episodes separated by 10 min of reperfusion) on day 1. On day 2, ischemia was induced with 30 min of ischemia and 120 min of reperfusion in IP and control rats. Results: IP rats showed decreased myocardial infarction (MI) area vs. non-IP control rats (15.32 vs. 45.6%). Furthermore, IP rats had preserved cardiac function (heart rate, rate pressure product, coronary flow and aortic flow) and myocardial ATP (P<0.03), decreased tissue water content (73.2 vs. 90.6%), increased expression of Bcl-2, and less mitochondrial swelling, cytochrome C release and apoptosis (2.6 vs. 12.4%) when compared to sham-operated rats. Activation of the permeability transition pore with PTP activators lonidamine (10 mg/kg body weight) or atractyloside (5 mg/kg body weight) before the sustained ischemia on day 2 resulted in complete abolition of SWOP-mediated cytoprotective effects. These agents had no effect on the cytoprotective effects that took place during the first window of preconditioning. Conclusion: The cytoprotective effects of SWOP are dependent on PTP activation state and may involve upregulation of Bcl-2 expression.
KEYWORDS Ion channels; Mitochondria; Membrane permeability; Preconditioning; Reperfusion
This article is referred to in the Editorial by G. Taimor (pages 266–267) in this issue.
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Myocardial protection from ischemia–reperfusion can be induced by exogenous [1] cardioprotective agents or by ischemic preconditioning (IP). Ischemic preconditioning (IP) is the phenomenon in which brief, non-lethal episodes of ischemia enhance the tolerance to more severe ischemia. Cardioprotection induced by IP exhibits a biphasic pattern. The first phase of preconditioning, commonly referred to as classical preconditioning [2], occurs immediately after the brief ischemia and may last up to 3 h. The second phase of preconditioning occurs 24 h after ischemia and may last up to 72 h. This latter phase is referred to as the ‘second window of ischemic preconditioning’ (SWOP) [3].
The opening of ATP sensitive potassium channels (KATP) plays a vital role in mediating protection during classical preconditioning. Various factors, including the activation of KATP channels, heat shock proteins, cytokines, oxygen radicals [4] and adenosine A1 receptor activation [5], have been proposed to mediate protection in the delayed phase of preconditioning. However, the exact mechanisms remain unknown. Hence understanding the mechanism underlying this protection will therefore give a clear view for adaptation of heart to ischemia and also will provide new strategies in preventing the myocardium after ischemic insult.
Ischemia–reperfusion injury induces changes in mitochondrial permeability via activation of the mitochondrial permeability transition pore (PTP) [6–8]. Subsequent mitochondrial calcium overload and oxidative stress result in adenine nucleotide depletion and compromised cell function [6,9]. Bcl-2, an anti-apoptotic protein localized to the outer mitochondrial membrane, can inhibit PTP opening and prevent the release of cytochrome c and apoptotic cell death [10].
The present study characterizes the relationship between mitochondrial PTP activation state, Bcl-2 expression, and the development of tolerance to ischemia–reperfusion injury during SWOP. We utilize a rat left coronary artery model of ischemia–reperfusion and the PTP activators, lonidamine [11] and atractyloside [12], to investigate our hypothesis.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Male Wistar rats weighing between 270 and 300 g were maintained on a 12-h dark/light cycle, housed at 21±1°C, and fed and watered ad libitum. The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Rats were anesthetized with phenobarbital 30 mg/kg, i.p., and intubated and ventilated with a small Harvard rodent ventilator (South Natick, MA, USA) with supplemental O2 set at a tidal volume of 2.0 ml/stroke and at a rate of 70 strokes/min. A lead electrocardiogram was monitored throughout the procedure.
Lonidamine and atractyloside was purchased from Sigma Japan. Lonidamine was dissolved in glucamine and diluted with saline. Atractyloside was dissolved in distilled water.
2.1 SWOP protocol
Left coronary artery (LCA) occlusion in rats was achieved as previously described [1]. On day 1, rats in the study group were subjected to IP protocols (four, 3-min episodes of LCA occlusion with 7-0 prolene suture, separated by 10 min of reperfusion). After the final reperfusion period, rats were randomly assigned to receive either intravenous infusion of the PTP activator lonidamine (10 mg/kg body weight, bw) [13] or atractyloside (5 mg/kg bw). Rats recovered from anesthesia, and postoperative analgesia was achieved with buprenorphine HCl (50 µg/kg, s.c.). Rats then returned to their cages without further manipulation. Sham-operated rats were utilized as control animals.
Twenty-four hours later, half of the animals were assigned to in vivo ischemia–reperfusion for the estimation of reperfusion injury and prevalence of apoptosis. The other half of animals were utilized for isolated heart ischemia–reperfusion in the Langendorf mode for myocardial ATP and mitochondrial evaluation.
2.2 In-vivo study
2.2.1 Myocardial infarction
Following systemic heparinization (500 IU/kg body weight of heparin sodium), the chest was reopened, and the LCA was occluded with the existing suture. After 30 min of ischemia, the ligature was released, and the heart was allowed to reperfuse for 120 min.
2.2.2 Infarct size assessment
At the end of reperfusion, the ligature around the LCA was retightened and 2 ml of 2% Evans blue dye was injected via the left femoral vein to estimate the area perfused by the occluded artery. The area at risk was determined by negative staining with the Evans blue, and the infarcted area was determined as the unstained area among the risk area following 1% triphenyl tetrazolium chloride (TTC) staining. The area of infarcted tissue and the risk zone were determined using the ‘IP’ lab software (Scanalytics, Version 3), and the infarct size was expressed as a percentage of the total LV and as the percentage of the risk area.
2.2.3 Immunohistochemistry
Cryostat-frozen sections were processed for apoptosis determination using anti-single stranded DNA (ssDNA) (Dako Japan) [14] as the primary antibody. Immunohistochemistry was carried out with the ABC staining system (Nichirei, Japan) according to the manufacturer's protocol
2.2.4 Western blotting analysis for Bcl-2
Frozen tissue samples from the risk area were homogenized in tissue lysis buffer [10 mM Tris (pH 7.4), 150 mM NaCl, 1% Triton X-100, 1% deoxycholate, 0.1% SDS, 5 mM EDTA, 1 mM phenylmethylsulfonylfluoride, 1 mM benzamidine,0.28 U/ml aprotinin, 50 µg/ml leupeptin, and 0.7 µg/ml pepstatin] and clarified by centrifugation at 14 000xg for 20 min at4°C. Proteins were measured with the BCA assay (Sigma Japan). Equal amounts of protein (50 µg) were run on 15% SDS–polyacrylamide gel. Western blot was performed as described previously [15] with primary antibody against Bcl-2 (1:1600, Sigma Japan) and, antimouse IgG conjugated with horseradish peroxidase (Santa Cruz Biotechnology) as the secondary antibody. Detection of protein-bound antibody was performed via ECL detection system (Amersham Pharmacia Biotech), according to the manufacturer's instructions.
2.3 Ex-vivo study
2.3.1 Regional ischemia–reperfusion:
The heart was rapidly excised and perfused according to the Langendorf technique at a constant pressure of 80 cmH2O with Krebs–Henseleit (KH) buffer containing NaCl (118 mmol/l), KCl (4.7 mmol/l), MgSO4 (1.2 mmol/l), KH2PO4 (1.2 mmol/l), CaCl2 (1.7 mmol/l), NaHCO3 (24 mmol/l) and glucose (11.0 mmol/l), equilibrated with 95% O2 and 5% CO2 at 37°C. The index of myocardial function, heart rate and aortic pressure, was continuously recorded with a direct-pressure amplifier (San-ei, USA). Coronary flow was calculated from the coronary effluent and aortic flow measured using an electromagnetic blood flow meter (Nihon Kohden, Japan). Left ventricle stroke volume (SV), stroke work (SW) and left ventricular (LV) power were calculated using the equations described earlier [16]
After calculation of baseline data and a 20-min equilibration period, hearts were subjected to 30 min of regional ischemia by tightening the existing suture, followed by 120 min of reperfusion. Hemodynamic parameters were measured every 10 min.
2.3.2 Estimation of tissue water content
A portion of the ventricular tissue in the area at risk was weighed after 120 min of reperfusion and then reweighed after the tissue had been dried at 80°C and at ambient pressure for 24 h. Myocardial water content was calculated as described earlier [17].
2.3.3 Myocardial metabolite analysis
The frozen ventricular tissue samples from the area at risk were crushed, the cells lysed with Tris–EDTA buffer at pH 7.4. ATP assay was performed using a bioluminescence luminometer (Lumat, LB9501, Germany) and a commercially available ATP bioluminescence kit (Promega, Japan) [18].
2.3.4 Mitochondrial swelling and cytochrome c release assay
The mitochondria were isolated from the risk area, as described earlier [19]. Mitochondrial swelling was measured by the decrease in absorbency at 520 nm, using a UV–Visible scanning spectrophotometer (Pharmacia Biotech, Ultrospec3000) after incubation of mitochondria at 25°C in buffer containing 300 mM sucrose, 10 mM MOPS, pH 7.4 with Tris. The optical density for the cytochrome c spectrum was recorded as a reference from 390 to 600 nm.
2.4 Experimental protocol
An identical protocol was followed in both modes of ischemia–reperfusion. Each mode included 10 groups. All hearts were subjected to 30 min of regional ischemia and 120 min of reperfusion (Fig. 1).
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Group 1: a sham group underwent anesthesia, the chest was opened, and a 7-0 suture was passed beneath the left coronary artery without IP protocol. On day 2, these rats were subjected to 30 min ischemia and 120 min reperfusion (n = 7).
Group 2: an IP group was subjected to 30 min ischemia and 120 min reperfusion immediately following the preconditioning episodes (n = 10).
Groups 3 and 4: animals were treated with intravenous infusion of lonidamine (10 mg/kg body weight) (group 3) or atractyloside (group 4) following the final episode of IP and immediately subjected to ischemia–reperfusion (n = 7, each).
Group 5: an intermediate IP group underwent the same protocol of ischemia–reperfusion as above after 5 h of preconditioning episodes (n = 10)
Group 6: a SWOP group underwent IP protocols on day 1, and the hearts were subjected to ischemia–reperfusion on day 2 (n = 8).
Group 7: SWOP with lonidamine group, in which animals were treated with intravenous infusion of lonidamine (10 mg/kg body weight) over a period of 30 min before the heart was subjected to ischemia–reperfusion on day 2 (n = 10).
Group 8: SWOP with atractyloside group, in which animals were treated with atractyloside (5 mg/kg body weight) as an intravenous infusion 30 min before the hearts were subjected to ischemia–reperfusion on day 2 (n = 8).
Groups 9 and 10: Rats were subjected to ischemia–reperfusion after treatment with lonidamine (10 mg/kg body weight; group 7) or atractyloside (5 mg/kg body weight; group 8) intravenously without IP protocol (n = 6, each group).
2.5 Statistical analysis
All results are expressed as means±S.E. Differences in hemodynamics were evaluated using two-way ANOVA. The other parameters were analyzed by one-way ANOVA followed by the Tukey–Kramer multiple test. A P value of less than 0.05 was considered statistically significant.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1 In-vivo study
3.1.1 Infarct size
Preconditioning resulted in a 66% reduction of infarct size compared to sham-operated hearts (15.3 vs. 45.6% infarct area, SWOP to sham, P<0.001). Treatment of preconditioned rats with lonidamine or atractyloside resulted in significant increase in the infarct size to 49.4 and 47.45%, respectively (P<0.001 compared to no drug treatment). Vehicle administration had no significant effect on infarct size. Lonidamine or atractyloside administration had no significant effect on infarct size in rats that did not undergo the IP protocols. Similarly, PTP agonists failed to eliminate the protective effects of the first window IP (Fig. 2).
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3.1.2 Prevalence of apoptosis
As expected, preconditioning reduced the prevalence of apoptotic cells to 2.6% compared to 12.4% in the sham-operated group. Lonidamine or atractyloside treatment yielded apoptotic frequencies of 10.3 and 11.5%, respectively. PTP agonists had no effect in the absence of IP protocols or in sham-operated rats. They and also failed to inhibit the protection during first window IP (Fig. 3).
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3.1.3 Bcl-2 expression
Western analysis revealed significant increase of Bcl-2 expression in the SWOP hearts compared to the normal or sham hearts. Lonidamine or atractyloside pretreatment attenuated Bcl-2 expression (Fig. 4).
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3.2 Ex-vivo study
3.2.1 Hemodynamics
SWOP resulted in significantly increased hemodynamic recovery. Lonidamine or atractyloside administration inhibited hemodynamic recovery (Tables 1 and 2
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3.2.2 Tissue water content
Myocardial tissue water content was 89.7% in the sham-operated group. SWOP resulted in the reduction of myocardial tissue water content in this group to 73.2% (P<0.02, from the sham-operated group). There was no significant difference in the tissue water content when comparing the first and second window IP (72.4 vs. 73.2%, P >0.05).
Treatment with lonidamine or atractyloside resulted in elevation of tissue water content to 90.4 and 90.2%, respectively (P<0.03, from the preconditioned group). Treatment with vehicle alone had no significant effect. PTP agonists had no effect on the protective effects during first window IP (Table 3).
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3.2.3 Myocardial ATP content
Fig. 5 and Table 3 show myocardial ATP content in the risk area of the study groups. The ATP levels in the preconditioned SWOP group were significantly higher than in sham-operated rats (0.87x10–8 vs. 0.18x10–8 mol/g wet weight; P<0.03). The first window IP group had ATP levels that were not significantly different from the SWOP group. Pretreatment with lonidamine or atractyloside abolished the SWOP-mediated increase in myocardial ATP level (0.127x10–8 vs. 0.13x10–8 mol/g wet weight). Treatment with vehicle had no alteration on preconditioning effect.
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3.2.4 Mitochondrial swelling and cytochrome c release
SWOP prevented mitochondrial swelling (Fig. 6) (P<0.05) and cytochrome c release from the mitochondria (P<0.05) (Fig. 7). Administration of PTP agonists resulted in swelling of mitochondria and release of cytochrome c with a peak at 414 nm.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The present study demonstrated that PTP contributed to protection during the second window of ischemic preconditioning. Furthermore, delayed preconditioning prevented the loss of myocardial ATP following reperfusion and prevented apoptosis by increasing Bcl-2 expression.
Many studies have shown a role for mitochondria in reperfusion injury following ischemia [7,8]. During reperfusion, cellular calcium increases, resulting in opening of the mitochondrial permeability transition pore [6,20] and release of cytochrome c. Subsequent activation of caspases results in the failure of ATP generation and mitochondrial membrane potential and leads to cell death.
PTP is formed by the apposition of transmembrane proteins from the inner and outer mitochondrial membranes at the contact sites between two membranes [21]. The impermeability of the mitochondrial inner membrane to all but a few selected metabolites is essential to maintain the membrane potential, which drives the ATP synthesis during phosphorylation.
Wang et al. [22] have demonstrated that IP reduces mitochondrial Ca2+ concentrations, a major consequence in reperfusion injury, while Halestrap [6] reported that elevated cellular Ca2+ induces PTP opening and leads to cell death. Moreover, Laclau et al. [23] demonstrated, decreased cytochrome c release (which usually occurs due to the opening of PTP [24]) at preconditioning. Therefore, PTP is a likely candidate to mediate delayed protection following ischemic preconditioning. Lonidamine [13,25] activates PTP and induces apoptosis. Ravagnan et al. [11] reported that Bcl-2 inhibited lonidamine-induced apoptosis by preventing PTP opening. Atractyloside [12] is a derivative from thistles, shown to inhibit the oxidative phosphorylation by blocking the adenine nucleotide transfer across the membranes and thereby opening the PTP [12].
The present study demonstrated that preconditioning resulted in significant protection of heart functions from ischemic injury and confirmed the occurrence of SWOP in rats. This protective effect was completely inhibited by lonidamine or atractyloside, suggesting a role of PTP in this process. Other parameters of tissue and cellular integrity followed similar patterns, including infarction area, heart rate and rate pressure product, myocardial water content, myocardial ATP levels, Bcl-2 expression, cytochrome c release and frequency of apoptotic cells. However, PTP agonists did not prevent protective effects of the first window IP.
DiBoana and Powell [26] showed a strong correlation between cell swelling and necrosis in ischemic dog myocardium. In the present study, lonidamine or atractyloside treatment resulted in higher tissue water content. Thus, SWOP may prevent cell swelling following the ischemia–reperfusion. Jennings et al. [27] reported that mitochondrial Ca2+ accumulation results in the cessation of ATP synthesis and leads to irreversible cell injury. Crompton et al. [28] have shown that this failure of ATP generation is preceded by PTP opening. Our previous study has also demonstrated the direct relation between myocardial ATP content and extent of myocardial damage [1]. In the present study, preconditioning resulted in maintenance of myocardial ATP levels following reperfusion. Furthermore, the effect of preconditioning was abolished by PTP agonists. Thus, mitochondrial pore activation state is a critical variable in the protective effect of delayed preconditioning.
Bcl-2 prevents PTP-mediated depolarization and inhibits cytochrome c release [23], and Martinou et al. [29] report that the most common mode of cytochrome c release is secondary to reduced Bcl-2 expression. In the present study, SWOP resulted in increased Bcl-2 expression and decreased mitochondrial swelling, cytochrome c release and apoptosis. In contrast, administration of PTP agonists before ischemia–reperfusion resulted in the marked reduction in Bcl-2 expression and increased mitochondrial swelling, cytochrome c release and apoptosis. These data support a role for PTP in the development of delayed protection following the IP.
With above results, it is possible to argue that opening of PTP could also result in the myocardial damage during the first window of protection. But, lonidamine or atractyloside administration failed to eliminate the protective effects of first window IP, thus making it unlikely that the PTP mediates myocardial damage during the first window of protection.
In summary, SWOP results in upregulation of Bcl-2 expression, thereby preventing PTP opening and mediating the second window of protection against reperfusion injury. Furthermore, delayed protection prevented apoptotic cell death, likely via inhibition of cytochrome c release.
Time for primary review 25 days.
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Acknowledgements |
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This study was supported in part by Grants-in-Aid from the Ministry of Education, Science, and Culture, Japan.
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