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Ischemic preconditioning produces more powerful anti-inflammatory and cardioprotective effects than limb remote ischemic postconditioning in rats with myocardial ischemia-reperfusion injury

ZHANG, Jia-qiang; WANG, Qiang; XUE, Fu-shan; LI, Rui-ping; CHENG, Yi; CUI, Xin-long; LIAO, Xu; MENG, Fan-min

doi: 10.3760/cma.j.issn.0366-6999.20130785
Original article
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Background Both ischemic preconditioning (IPC) and limb remote ischemic postconditioning (LRIPOC) have been shown to possess significantly different cardioprotective effects against the myocardial ischemia reperfusion injury (IRI), but no study has compared the anti-inflammatory effects of IPC and LRIPOC during myocardial IRI process. We hypothesized that IPC and LRIPOC would produce different anti-inflammatory effects in an in vivo rat model with myocardial IRI.

Methods Eighty rats were randomly allocated into four equal groups: sham group, IRI group, IPC group and LRIPOC group. In 10 rats randomly selected from each group, serum levels of TNF-α, HMGB1, ICAM1, IL-1, IL-6 and IL-10 were assessed, and infarct size was determined. In another 10 rats of each group, myocardial levels of TNF-α, HMGB1, ICAM1, IL-1, IL-6 and IL-10 in both ischemic and non-ischemic regions were measured.

Results The infarct size was significantly lower in IPC and LRIPOC groups than in IRI group. The serum and myocardial levels of pro-inflammatory cytokines including TNF-α, HMGB1, ICAM1, IL-1 and IL-6 during reperfusion were significantly reduced in IPC and LRIPOC groups compared to IRI group. As compared to the IPC group, infarct size, serum level of TNF-α at 60 minutes of reperfusion, serum levels of HMGB1 and ICAM1 at 120 minutes of reperfusion, myocardial levels of TNF-α, ICAM1, IL-1 and IL-6 in the ischemic region, myocardial levels of ICAM1, IL-1 and IL-6 in the non-ischemic region were significantly increased in the LRIPOC group.

Conclusions In the rats with myocardial IRI, IPC produces more powerful inhibitory effects on local myocardial and systemic inflammatory responses than LRIPOC. This may be partly attributed to more potent cardioprotection produced by IPC.

Department of Anesthesiology, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China (Zhang JQ and Meng FM)

Department of Anesthesiology, Peking University People's Hospital, Beijing 100044, China (Wang Q and Liao X)

Department of Anesthesiology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China (Xue FS, Li RP, Cheng Y and Cui XL)

Correspondence to: Dr. XUE Fu-shan, Department of Anesthesiology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China (Email: xuefushan@aliyun.com)

ZHANG Jia-qiang and WANG Qiang contributed equally to this work.

This research was funded by the National Natural Science Foundation of China (No. 30972836).

(Received March 27, 2013)

Edited by CHEN Li-min and PAN Cheng

It has been demonstrated that myocardial ischemia reperfusion injury (IRI) is responsible for up to 50% of final size of a myocardial infarction,1 and the mortality rate attributed to the IRI after an acute myocardial infarction is up to 10%.2 As a result, targeting IRI will definitely be a promising strategy for cardiac protection.1,3 It has been widely accepted that ischemia preconditioning (IPC) is the most powerful endogenous protective strategy against myocardial IRI.4 However, its clinical application is hampered by the requirement to implement the ischemic stimulus before onset of acute myocardial ischemia, which is obviously impossible in clinical settings.5 Moreover, the classic IPC can lead to dangerous complications including diseased coronary artery rupture and atheromatous plaque falling off, which can lead to direct intervention in the heart.5 Remote ischemic postconditioning (RIPOC), which is still cardioprotective when applied to an organ or tissue away from the heart, can overcome the aforementioned problems associated with IPC.5,6 With the flexibility of being a noninvasive intervention, limb remote ischemic postconditioning (LRIPOC) is able to be applied in a wide variety of clinical settings for myocardial IRI patients.5

The available evidence shows that an inflammatory response plays a fundamental pathogenic role in myocardial IRI.7–9 The therapies aimed at inhibiting inflammation during myocardial IRI process have been provn to produce a significant reduction in final infarct size.7,10 Recent studies have demonstrated that the IPC can inhibit the inflammatory response during myocardial IRI process, mitigating the myocardial IRI.11,12 LRIPOC has also been shown to possess a potent endogenous infarct size sparing effect against the IRI by blocking infiltration of neutrophils into damaged cardiac tissues.13 Previous studies have suggested that IPC and LRIPOC share mechanistic similarities, with both interventions activating the reperfusion injury salvage kinase (RISK) signal transduction pathway14,15 though IPC can confer a more potent cardioprotection than LRIPOC.14 To the best of our knowledge, however, there is no study comparing the anti-inflammatory effects of IPC and LRIPOC during the myocardial IRI process. Therefore, this randomized controlled experiment was designed to assess the differences between IPC and LRIPOC in anti-inflammation and cardioprotection during the myocardial IRI process in an in vivo rat model.

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METHODS

Surgical preparation of animals

Male Sprague-Dawley rats, aged 8 weeks and weighing 290-320 g, were used in this study. Animals were placed in a quiet, temperature ((22 ± 2) °C) and humidity ((60 ± 6)%) controlled room with a 12:12 hours light-dark cycle (light beginning at 8 a.m.), and all tests were performed during the light phase of the cycle. This study was conducted in accordance with our institutional guidelines of the use of live animals for research, and the experimental protocol was approved by the Animal Care and Use Committee of the Peking Union Medical College.

The acute myocardial IRI model was established, as previously described.16 The animal was trachealy intubated and mechanically ventilated with oxygen-enriched room air using a rodent respirator. Arterial blood gases were maintained at normal levels by adjusting the ventilation rate and tidal volume. The body temperature was maintained at 36.5-37.5 °C by a heating pad. The left internal jugular vein was cannulated for blood sampling to assay serum levels of troponin I (TnI), creatine kinase-myocardial band isoenzyme (CK-MB), tumor necrosis factor α (TNF-α), high mobility group box 1 protein (HMGB1), intercellular adhesion molecule 1 (ICAM1), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-10 (IL-10). The left carotid artery was cannulated for monitoring arterial pressure with a MP150 data acquisition and analysis system (Biopac Systems Inc., CA, USA). The lead electrocardiogram (ECG) and heart rate (HR) were continuously recorded by means of needle electrodes placed subcutaneously on the limbs.

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Experimental protocol

Eighty rats were randomly assigned to four groups subjected to different protocols (n=20 in each group): sham group, IRI group, IPC group and LRIPOC group (Figure 1). All rats had the chest opened, and the left anterior descending coronary artery (LAD)was encircled with a suture. In the groups other than the sham group, the LAD was ligated for 30 minutes followed by a 120-minute reperfusion in vivo. In the IRI group, no additional intervention was performed. In the IPC group, animal underwent three consecutive 5-minute LAD occlusions followed by a 5-minute reperfusion, which was performed before a 30-minute LAD ligation followed by a 120-minute reperfusion.17 In the LRIPOC group, a thin elastic rubber tourniquet was placed around the upper third of each hindlimb at 20 minutes of myocardial ischemia period to occlude arterial blood flow for 10 minutes, and then the limb reperfusion was achieved by releasing tourniquet at the time when the myocardial reperfusion was commenced.15 Then, the rats in each group were randomly divided equally into subgroup A and subgroup B (n=10 in each subgroup). In the subgroup A, blood samples were taken at 30 minutes, 60 minutes and 120 minutes of reperfusion for analysis of serum TnI, CK-MB, and inflammatory cytokines. At the end of the experiment, infarct size (IS%) was assessed from excised heats by Evans blue and triphenyltetrazolium chloride (TTC) staining. After a reperfusion period of 120 minutes in the subgroup B, the tissue pieces of the left (ischemic region) and right (non-ischemic region) ventricles were excised for later measurements of inflammatory cytokine levels in the myocardial tissues.

Figure 1.

Figure 1.

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Observed variables

After a stabilization period of 10 minutes, HR and mean arterial pressure (MAP) were taken as the baseline values. In addition, HR and MAP were recorded at the beginning (0 minute), 10 minutes and 20 minutes of ischemia and 30 minutes, 60 minutes and 120 minutes of reperfusion. The rate pressure product (RPP) at every measuring point was calculated as the index of myocardial oxygen consumption.

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Evaluation of infarct size

After a reperfusion period of 120 minutes in the subgroup A, the infarct size was assessed by Evans blue and triphenyltetrazolium chloride staining, as previously described.8,16

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Measurements of serum TnI, CK-MB and inflammatory cytokines

In the subgroup A, blood samples collected in tubes containing microscopic silica particles were rested for 30 minutes, and then centrifuged at 3000 r/min for 15 minutes. The supernatants were collected and stored at -80 °C until future analysis. The serum levels of TnI, CK-MB, TNF-α, HMGB1, ICAM1, IL-1, IL-6 and IL-10 were assessed using the enzyme-linked immunosorbent assay (ELISA) kits special for rat by a blinded investigator, according the manufacturer's instructions (Rapidbio Co. Ltd, West Hills, CA, USA).

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Measurements of inflammatory cytokines in the myocardium

Myocardial tissues (100 mg) taken from the ischemic or non-ischemic region in the subgroup B were homogenized in 1000 μl ice-cold homogenization buffer. Homogenates were centrifuged at 3000 r/min for 10 minutes at 4°C. The supernatants were collected and stored at -80 °C for later detection of TNF-α, HMGB1, ICAM1, IL-1, IL-6 and IL-10 with the special enzyme-linked immunosorbent assay (ELISA) kits designed for rat experiment following the manufacturer's instructions (Rapidbio Co. Ltd). And the detection of myocardial cytokines was implemented by a blinded investigator. Inflammatory cytokine levels in the myocardial tissues were normalized to the protein concentration in the sample.

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Statistical analysis

Statistical analysis of data was performed with SPSS (Version 16.0, SPSS Inc., USA). If the data were normally distributed and had homogeneous variance, they were expressed as mean ± standard deviation (SD). One-way analysis of variance (ANOVA) was used to compare the data among groups. Repeated-measures ANOVA were applied for within-group comparisons. Tukey's multiple comparison test was used for post hoc multiple comparisons. When data were not normally distributed or had inhomogeneous variance, they were expressed as median (interquartile range) and compared by using the Kruskal-Wallis test and Mann-Whitney U test. The criterion for rejection of the null hypothesis was P < 0.05 for all tests.

The hypothesis of this study was that there would be 20% differences among the IRI, IPC and LRIPOC groups in the infarct size, serum and myocardial pro-inflammatory cytokine levels. Power calculation indicated that a sample size of at least eight rats per group would be required, with a power of 80% and P value of 0.05. More than eight rats per group were included in the study so as to ensure enough data to fit the ANOVA models and to allow for comparisons among other outcome variables of interest.

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RESULTS

Basic data and hemodynamics

The body weight, body temperature after anesthesia, and baselines of HR, MAP and RPP did not differ among the four groups. Hemodynamic changes with the ischemia reperfusion process in the four groups are shown in Table 1. All hemodynamic variables in sham group did not change significantly throughout the observation. Compared to the baselines, MAP and RPP at the initiation of ischemia in IRI, IPC and LRIPOC groups decreased significantly. After 10 min of ischemia, MAP and RPP in IRI, IPC and LRIPOC groups returned to the baseline levels. MAP and RPP at the initiation of ischemia were significantly lower in IRI, IPC and LRIPOC group than in sham group. However, there was no significant difference in HR at each measuring point among the four groups.

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Myocardial infarct size and serum TnI and CK-MB levels

The areas at risk and infarct sizes are shown in Figure 2. Infarct size and serum level of CK-MB were significantly increased in IRI, IPC and LRIPOC groups compared to sham group. Serum level of TnI was significantly higher in IRI and LRIPOC groups than in the sham group. Compared to IRI group, infarct size and serum levels of TnI and CK-MB significantly decreased in IPC and LRIPOC groups. Compared to IPC group, infarct size and serum levels of TnI and CK-MB were significantly increased in LRIPOC group (Table 2).

Figure 2.

Figure 2.

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Serum inflammatory cytokine levels

The serum levels of inflammatory cytokines are shown in Figure 3. As compared to sham group, serum levels of TNF-α at 30 minutes, 60 minutes and 120 minutes of reperfusion, serum levels of HMGB1 at 60 minutes and 120 minutes of reperfusion, and serum levels of ICAM1, IL-1 and IL-6 at 120 minutes of reperfusion were significantly increased in IRI group. Also, serum level of HMGB1 at 60 minutes of reperfusion, serum levels of IL-1 and IL-6 at 120 minutes of reperfusion were significantly higher in IPC group than in sham group. However, serum levels of TNF-α at 60 minutes and 120 minutes of reperfusion were significantly lower in IPC group than in sham group. And serum level of TNF-α at 30 minutes of reperfusion, serum levels of HMGB1 at 60 minutes and 120 minutes of reperfusion, and serum levels of ICAM1, IL-1 and IL-6 at 120 minutes of reperfusion were significantly higher in LRIPOC group than in sham group. However, serum level of TNF-α at 120 minutes of reperfusion was significantly lower in LRIPOC group than in sham group.

Figure 3.

Figure 3.

Compared to IRI group, serum levels of TNF-α at 30 minutes, 60 minutes and 120 minutes of reperfusion, serum levels of HMGB1 at 60 minutes and 120 minutes of reperfusion, serum levels of ICAM1, IL-1 and IL-6 at 120 minutes of reperfusion were significantly decreased in IPC group. Also, serum levels of TNF-α at 30 minutes, 60 minutes and 120 minutes of reperfusion, serum levels of HMGB1, ICAM1, IL-1 and IL-6 at 120 minutes of reperfusion were significantly lower in LRIPOC group than in IRI group.

Compared to IPC group, serum level of TNF-α at 60 minutes of reperfusion, serum levels of HMGB1 and ICAM1 at 120 minutes of reperfusion were significantly increased in LRIPOC group. However, there was no difference in serum level of IL-10 at 120 minutes of reperfusion among sham, IRI, IPC and LRIPOC groups.

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Myocardial inflammatory cytokine levels in the ischemic region (Figure 4)

Figure 4.

Figure 4.

Myocardial levels of TNF-α, HMGB1, ICAM1, IL-1, IL-6 and IL-10 were significantly increased in IRI group compared to sham group. Myocardial level of IL-10 significantly higher in the IPC group than in sham group, but myocardial level of TNF-α was significantly lower in IPC group than in sham group. As compared to the sham group, myocardial levels of ICAM1, IL-1, IL-6 and IL-10 were significantly increased in LRIPOC group.

As compared to the IRI group, myocardial levels of TNF-α, HMGB1, ICAM1, IL-1 and IL-6 were significantly decreased in IPC and LRIPOC groups. Myocardial levels of TNF-α, ICAM1, IL-1 and IL-6 were significantly higher in LRIPOC group than in IPC group. However, myocardial level of IL-10 did not significantly differ among the IRI, IPC and LRIPOC groups.

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Myocardial inflammatory cytokine levels in the non-ischemic region (Figure 4)

As compared to sham group, myocardial levels of TNF-α, HMGB1, ICAM1, IL-1, IL-6 and IL-10 were significantly increased in IRI group. Myocardial levels of IL-1 and IL-10 were significantly higher in IPC group than in the sham group, but myocardial levels of HMGB1, ICAM1 and IL-6 were significantly lower in IPC group than in sham group. Compared to sham group, myocardial levels of IL-1, IL-6 and IL-10 were significantly increased and myocardial level of HMGB1 was significantly decreased in LRIPOC group.

As compared to IRI group, myocardial levels of TNF-α, ICAM1, IL-1 and IL-6 were significantly decreased in IPC group, and myocardial levels of TNF-α, HMGB1, ICAM1, IL-1 and IL-6 were significantly decreased in LRIPOC group, but myocardial levels of ICAM1, IL-1 and IL-6 were significantly increased in LRIPOC group than in IPC group. There was no significant difference in myocardial level of IL-10 among IRI, IPC and LRIPOC groups.

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DISCUSSION

The principal findings of this study included: (1) Both IPC and LRIPOC could significantly suppress the inflammatory response during the myocardial IRI process, as shown by decreased serum and myocardial levels of pro-inflammatory cytokines such as TNF-α, HMGB1, ICAM1, IL-1 and IL-6. However, IPC produced a stronger anti-inflammatory effect than LRIPOC. (2) Both IPC and LRIPOC could provide significant protection against myocardial IRI, as evidenced by reduced infarct size and serum TnI and CK-MB levels. However, cardioprotection of the IPC was stronger than that of LRIPOC.

The results of this study showed that infarct size, and serum TnI and CK-MB levels were significantly increased in IRI group than in sham group, indicating the successful establishment of a myocardial IRI model. Our results also showed that compared to sham group, serum levels of TNF-α at 30 minutes, 60 minutes and 120 minutes of reperfusion, serum levels of HMGB1 at 60 minutes and 120 minutes of reperfusion, serum levels of ICAM1, IL-1 and IL-6 at 120 minutes of reperfusion, and myocardial levels of TNF-α, HMGB1, ICAM1, IL-1 and IL-6 in both ischemic and non-ischemic regions were significantly increased in IRI group. These findings imply that myocardial IRI can induce significant local and systemic inflammatory responses, which is in agreement with the results of previous studies.10–12

Inflammatory response is one of important mechanisms for myocardial IRI.7 It has been demonstrated that myocardial IRI can cause nuclear translocation of the nuclear factor-κB (NF-κB) complex from the cytosol in a very early stage of reperfusion,18 which further led to elevation of serum proinflammatory cytokines, such as TNF-α and IL-6.19 Also, the TNF-α released during myocardial IRI process can induce a cascade reaction of pro-inflammatory cytokines, which further increases the formation of pro-inflammatory cytokines, such as IL-1 and IL-6.20 Subsequently, increased serum pro-inflammatory cytokines result in Ca2+ dyshomeostasis in the cardiocytes, decreasing the myocardial contractile function.20 In addition, up-regulation of TNF-α in the ischemic myocardium is able to induce mitochondria damage evidenced by mitochondria swelling, disruption of crista and reduced density, which would ultimately induce irreversible myocardial IRI.21 A recent study confirms that HMGB1 can function as a mediator to modulate inflammatory response and cell injury during the early stage of myocardial IRI as well as the classic early pro-inflammatory cytokines, such as TNF-α and IL-6. Moreover, HMGB1 is able to promote the release of TNF-α and IL-6, and consequently, deteriorated the myocardial IRI.22 It has been shown that ICAM1 can mediate leukocyte adhesion and subsequent infiltration into the infarct area. By subsequent releasing free radicals and pro-inflammatory cytokines, activated leukocytes ultimately result in myocardial damage.23 These findings of the previous studies indicate that myocardial IRI can not only induce significant local and systemic inflammatory responses, but also inflammatory response can conversely aggravate the myocardial IRI.

Our results showed that compared to IRI group, serum levels of TNF-α at 30 minutes, 60 minutes and 120 minutes of reperfusion, serum levels of HMGB1 at 60 minutes and 120 minutes of reperfusion, and serum levels of ICAM1, IL-1 and IL-6 at 120 minutes of reperfusion were significantly decreased in IPC group. Moreover, myocardial levels of TNF-α, HMGB1, ICAM1, IL-1 and IL-6 in the ischemic region, and myocardial levels of TNF-α, ICAM1, IL-1 and IL-6 in the non-ischemic region were lower in IPC group than those in IRI group. These findings reveal that IPC can significantly inhibit myocardial local (both ischemic and non-ischemic regions) and systemic inflammatory responses during myocardial IRI process, which are in accordance with the results of previous studies.11,12

Heretofore, there has been no study having evaluated the effects of LRIPOC on both local and systemic inflammatory responses during myocardial IRI process. Our results showed that compared to IRI group, serum levels of TNF-α at 30 minutes, 60 minutes and 120 minutes of reperfusion, serum levels of HMGB1, ICAM1, IL-1 and IL-6 at 120 min of reperfusion, myocardial levels of TNF-α, HMGB1, ICAM1, IL-1 and IL-6 in both ischemic and non-ischemic regions were significantly decreased in LRIPOC group. This indicates that as with IPC, LRIPOC can also obviously attenuate myocardial local (both ischemic and non-ischemic regions) and systemic inflammatory responses during myocardial IRI process. However, compared to IPC group, serum level of TNF-α at 60 minutes of reperfusion, serum levels of HMGB1 and ICAM1 at 120 minutes of reperfusion, myocardial levels of TNF-α, ICAM1, IL-1 and IL-6 in the ischemic region, and myocardial levels of ICAM1, IL-1 and IL-6 in the non-ischemic region were significantly increased in LRIPOC group. These results suggest that compared with LRIPOC, IPC produces a more powerful inhibitive effect on myocardial local and systemic inflammatory responses during myocardial IRI process.

It is generally believed that both IPC and LRIPOC appear to share some common signaling pathways in exerting cardioprotection.12,14,15 Additionally, some studies revealed that both IPC and LRIPOC attenuated myocardial IRI by suppressing neutrophils infiltration into damaged cardiac tissues.13 Similarly, our study showed that both IPC and LRIPOC significantly reduced local myocardial and systemic inflammatory responses during myocardial IRI process, and IPC produced a more potent anti-inflammatory effect compared to LRIPOC. Moreover, compared to LRIPOC group, infarct size and serum levels of TnI and CK-MB were significantly decreased in IPC group, suggesting a more powerful cardioprotective effect produced by IPC. Thus, we infer that more potent cardioprotection of IPC compared to LRIPOC should partly attribute to its more powerful anti-inflammatory effect.

It has been demonstrated that strength of the protective effect afforded by IPC24 or LRIPOC25 is related to tissue volume exposed to protocol of ischemic stimulus, duration of ischemia and numbers of circles. Thus, a limitation of our study design is that only anti-inflammatory and cardioprotective effects of a single protocol of IPC or LRIPOC are assessed. We believe that if the other protocols of IPC or LRIPOC are used, different results are likely to be obtained. Another limitation of our study is that serum levels of TnI and some inflammatory cytokines were only measured at a single time point. This may be insufficient to depict the panorama of myocardial injury and kinetic features of some inflammatory cytokines. However, the total blood volume of a rat restricts the quantity of sampled blood for assay of these biomarkers at all measuring points. Therefore, other than TNF-α and HMGB1, this study can not provide any clue for kinetics of other biomarkers during myocardial IRI process. These issues remain to be demonstrated by further research.

In conclusion, this study demonstrates that in an in vivo rat model with myocardial IRI, IPC produces a more powerful inhibitive effect on local myocardial and systemic inflammatory responses than LRIPOC. This may be partly contributed to a more potent cardioprotection produced by IPC compared to LRIPOC.

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Keywords:

myocardial ischemia-reperfusion injury; inflammatory response; ischemia preconditioning; limb remote; ischemic postconditioning

© 2013 Chinese Medical Association