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Cardiovascular Research 2005 65(1):239-243; doi:10.1016/j.cardiores.2004.10.003
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Copyright © 2004, European Society of Cardiology

Free radicals trigger TNF{alpha}-induced cardioprotection

Sandrine Lecoura,*, Luc Rochetteb and Lionel Opiea

aHatter Institute for Cardiology Research, Department of Medicine, University of Cape Town Medical School Observatory, 7925 Cape Town, South Africa
bLPPCE, Facultes de Medecine et Pharmacie, Dijon, France

* Corresponding author. Tel.: +27 21 406 63 58; fax: +27 21 447 87 89. Email address: Sandrine{at}capeheart.uct.ac.za

Received 20 July 2004; revised 14 September 2004; accepted 4 October 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Objective: Tumor Necrosis Factor {alpha} (TNF{alpha}) induces programmed cell death and contributes to cardiac ischemia/reperfusion injury. Paradoxically, we have recently demonstrated that low doses of TNF{alpha} can induce cardiac preconditioning (PC). We hypothesized that the production of free radicals participates in this cardioprotective program.

Methods: Control isolated rat hearts underwent 30 min regional ischemia and 120 min of reperfusion. A second group of hearts received a low dose of TNF{alpha} (0.5 ng/ml) for 7 min followed by 10 min washout prior to I/R. In other groups, the antioxidant N-2-mercaptopropionyl glycine (MPG) (1 mM) was given for 15 min prior to I/R alone or during TNF{alpha} perfusion. Infarct size was determined at the end of the reperfusion period. Ventricular catalase and superoxide dismutase activities were assessed as an index of oxidative stress and free radical production was directly measured by the oxidation of 1-hydroxy-3-carboxy-pyrrolidine (CP-H) to paramagnetic 3-carboxy-proxyl (CP.) using electron spin resonance spectroscopy.

Results: TNF{alpha} reduced the infarct/area at risk (I/AAR) ratio (7.2 ± 1.7% vs. 36.5 ± 1.7% for controls, p<0.05). MPG reduced the cardioprotective effect of TNF{alpha} (I/AAR ratio: 20.5 ± 3.3%, p<0.05). TNF{alpha}-perfusion increased catalase activity in the ventricles (15.8 ± 1.2 I.U./mg for controls vs. 19.9 ± 1.1 I.U/mg for TNF{alpha}, p<0.05). Proof of formation of free radicals was increased CP formation in the coronary effluent during TNF{alpha} infusion (24.2 ± 4.5 for TNF{alpha} vs. 11.9 ± 1.5 arbitrary units for controls, p<0.05), with decreased CP after addition of MPG.

Conclusions: Our data provide firm evidence for a production and role of free radicals in TNF{alpha}-induced cardioprotection.

KEYWORDS Cytokines; Ischemia; Oxygen radicals; Preconditioning; Reperfusion


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Tumor necrosis factor alpha (TNF{alpha}) is a multifunctional cytokine implicated as mediator of diverse physiologic and pathophysiologic events including inflammation, growth, differentiation and apoptosis. TNF{alpha} is thought to contribute to the development of myocardial disease, with direct correlation between serum TNF{alpha} and the severity and progression of heart failure [1,2]. However, recent clinical trials of anti-TNF{alpha} therapy for heart failure have been extremely disappointing [3,4] perhaps because of the possible dual role of TNF{alpha} in attenuation and aggravation of cardiac injury [5]. Recently, we have demonstrated that TNF{alpha}, in a dose- and time-dependent manner, could mimic ischemic preconditioning and thus lead to cardioprotection in a rat model [6]. This beneficial effect of TNF{alpha} has been confirmed by other investigators, using rabbit [7] or mouse [8] models. Furthermore, we have also shown that ischemic preconditioning was abrogated in TNF{alpha} knockout mice [9].

The signaling pathways involved in the cardioprotective effect of TNF{alpha} remain poorly understood. A reasonable hypothesis is that TNF{alpha} and ischemic preconditioning are protective via similar pathways. However, although sphingolipids are involved in TNF{alpha}-mediated preconditioning, they are not known to play a role in the preconditiong that follows transient global ischemia [6]. On the other hand, p38 MAP-kinase is involved in ischemic preconditioning, but plays no role in TNF{alpha}-induced preconditioning [8]. Recently, free radicals have been suggested as triggers to ischemic preconditioning (see Ref. [10]) and are known to be activated by TNF{alpha} [11]. The exact role of free radicals in ischemia and/or reperfusion remains controversial, mainly due to technical difficulties in their measurement. In the present study, we hypothesized that pre-ischemic free radical activation mediates TNF{alpha}-induced cardioprotection. Therefore, we examined the effect of the antioxidant, N-2-mercaptopropionyl glycine (MPG) on the resistance to myocardial infarction conferred by TNF{alpha} in the isolated rat heart system. We also assayed antioxidant enzyme activities. Furthermore, the formation of free radicals following TNF{alpha} stimulation was directly measured using electron spin resonance spectroscopy techniques.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Animal groups
All the experiments were conducted on adult male Long-Evans rats weighing 250–300 g in accordance with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85 (23), revised 1996) and all procedures were approved by the Faculty of Health Sciences Animal Ethics Committee, University of Cape Town.

2.2. Experimental protocols
Rats were anesthetized with 60 mg/kg intraperitoneal sodium pentobarbitone and were given an intravenous injection of 200 IU heparin. Hearts were excised rapidly and perfused retrogradely using the Langendorff technique at a constant pressure (100 cm H2O) with oxygenated Krebs–Henseleit buffer. A balloon was inserted through the left atrium into the left ventricle and the left-ventricular end diastolic pressure (LVEDP) was adjusted between 4 and 8 mm Hg. Cardiac parameters were monitored continuously and included heart rate (HR), left ventricular developed pressure (LVDP: difference between left ventricular end-systolic pressure and end-diastolic pressure) and the coronary flow (CF).

The perfusion protocol is shown in Fig. 1. All hearts were allowed to equilibrate for 15 min and were consequently subjected to a standard 30 min regional ischemia (induced by tightening a snare around the left coronary artery) followed by 120 min of reperfusion. A low dose of TNF{alpha} (0.5 ng/ml) was given for 7 min followed by a 10 min of wash out period before the standard ischemia. Additional groups were perfused with the free radical scavenger N-2-mercapto propionyl glycine (MPG; 1 mM) for 15 min followed by 5 min washout prior to the ischemia–reperfusion insult.


Figure 1
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  		Fig. 1 Treatment protocols for isolated perfused rat heart studies. TNF{alpha} (0.5 ng/ml), N-2-mercaptopropionyl glycine (MPG, 1mM).

 
For infarct size measurement, the coronary artery was reoccluded at the end of the reperfusion period and a solution of 2.5% Evans Blue was perfused to delinate the area at risk. Hearts were then frozen and cut into slices, incubated in sodium phosphate buffer containing 1% w/v triphenyltetrazolium chloride (TTC) for 15 min to visualize the unstained infarcted region. Infarct and risk zone areas were determined with planimetry and infarct was expressed as a percentage of the risk zone.

2.3. Free radical determination
On a separate set of hearts, free radical formation was determined in the coronary effluents using the spin probe 1-hydroxy-3-carboxy-pyrrolidine (CP-H) and electron spin resonance (ESR) spectroscopy analysis [12,13]. A fresh cold stock solution of CP-H (4 mM) was prepared in an oxygen-free 0.9% NaCl containing 50 µM deferoxamine to decrease the self-oxidation of hydroxylamines catalyzed by transition metal ions. CP-H was administered upstream of the heart with a mini pump with an infusion rate adjusted to 1/40th of the coronary flow, ensuring a final CP-H concentration at 0.1 µM. Samples of coronary effluents were collected at various times for further determination of CP levels with ESR spectroscopy. ESR spectra were recorded at 193 K with a Bruker ESP300R-X band spectrometer using TM 110 cavity and an aqueous flat cell. The ESR settings were as follows: microwave power, 20 mW; microwave frequency, 9.84 GHz; modulation amplitude, 2.0 G; modulation frequency, 100 KHz; conversion time, 81.92 ms; time constant, 655 ms. The CP content was evaluated from the spectrum ESR intensity and expressed in arbitrary units (A.U.)/ml of coronary flow.

2.4. Measurements of antioxidant enzymes activities
To evaluate catalase and total superoxide dismutase (SOD) activities, the heart was removed from the cannula and the atria were removed. The remainder of the heart was instantaneously frozen and kept at –80° until use. Afterwards, hearts were homogenized in 5 vol. of a 0.25 M sucrose solution and centrifuged at 6500 x g at 4°. The supernatant was then used for catalase determination with a modified method derived from Aebi and Clairbone [14]. Total SOD activities analysis was based on the method developed by Mc Cord and Fridovich, as previously described [14]. The enzymes activities were expressed in international units per mg of protein (IU/mg prot).

2.5. Pharmacologic agents
The spin probe CP-H was obtained from Noxygen (Elzach, Germany) and all other chemicals were obtained from Sigma.

2.6. Statistical analysis
Data are presented as mean ± SEM (n ≥ 6). Comparisons between multiple groups were performed by one-way ANOVA followed by the Student–Newman–Keul post hoc test (Graph Pad Instat). A value of p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Haemodynamic data and myocardial infarct size
Table 1 summarises haemodynamic data recorded in the four different experimental groups before the index ischemia, and during the ischemia–reperfusion insult. Left ventricular developed pressure, heart rate and coronary flow did not significantly differ among various groups. As shown in Fig. 2, control hearts subjected to 30 min regional ischemia and 120 min reperfusion had an infarct of 26.6 ± 3.1% (expressed as a percentage of the area of risk). Pretreatment of the hearts with TNF{alpha} (0.5 ng/ml) resulted in a reduction of the infarct size to 7.8 ± 1.7% (p<0.05 vs. control). When TNF{alpha} was perfused in the presence of the free radical scavenger MPG, the infarct sparing effect was lost, resulting in a similar infarct compared to the control hearts (26.4 ± 4.6 vs. 26.6 ± 3.1, p=n.s.).


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  		Table 1 Hemodynamic parameters of isolated perfused rat hearts

 

Figure 2
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  		Fig. 2 Effect of the antioxidant, N-2-mercaptopropionyl glycine (MPG: 1 mM) on the resistance to myocardial infarction conferred by TNF{alpha} (0.5 ng/ml). Infarct size was measured following 30 min occlusion of the left coronary artey and 120 min of reperfusion. *p<0.05 versus control.

 
3.2. Free radical determination
Experiments performed with ESR spectroscopy on coronary effluents showed the presence of a triplet (aN=16.1G, aH=1.7 G) attributed to the spectrum of CP. The amount of free radical species in the coronary effluent was reported in Fig. 3. During normoxic perfusion (Control group) a constant and low amount of free radicals was detected in the effluent. Addition of the free radical scavenger MPG significantly reduced the amount of free radicals species after 3 min of perfusion but came back to the same level than the control after the washout period. Free radicals release in the effluent was substantially increased in the presence of low dose of TNF{alpha} (0.5 ng/ml) for 7 min but came back to the same level than the control group after the 10 min of washout period. When TNF{alpha} was perfused in the presence of the antioxidant MPG, this increase of free radicals was lost.


Figure 3
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  		Fig. 3 Free radicals release during perfusion. CP levels detected in coronary effluents during preischemic normoxic perfusion (control) in the presence of TNF{alpha} (0.5ng/ml) and/or MPG (1mM). Results are expressed in arbitrary units (A.U.) and presented as mean ± SEM (n=6). *p<0.05 versus control group at the same time point.

 
3.3. Catalase and SOD activities analysis
Biochemical measurements (Fig. 4) of ventricles of hearts perfused with TNF for 7 min demonstrated that catalase activity was higher compared with the control group (19.9 ± 1.2 vs. 15.8 ± 1.2 IU/mg of protein, p ≥ 0.05). Total SOD activity measured at the same time point was unchanged in the presence of TNF{alpha} (11.3 ± 1.2 vs. 14.5 ± 3.8 IU/mg of protein for TNF{alpha} group, ns).


Figure 4
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  		Fig. 4 Determination of catalase and superoxide dismutase (SOD) activities in the isolated rat hearts. The activities were determined at the end of TNF{alpha} (0.5 ng/ml) perfusion. Results are expressed in international units (IU)/mg of protein. Each bar represents the mean ± SEM (n=10). *p<0.05 versus control.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
The combination of three findings strongly suggests that free radical signalling is involved in TNF{alpha}-induced cardioprotection. First, MPG lessened the infarct-reducing capacity of TNF{alpha}. Second, TNF{alpha} increased ventricular catalase activity. Third, and most important, direct measurement of free radical production by electron spin resonance spectroscopy showed a marked increase during but not after TNF{alpha}-perfusion (Fig. 3). Electron spin resonance is the most direct and sensitive method for detection of free radicals [15] and the spin probe technique that we used in our model (CP-H) detects superoxide and peroxynitrite [16,17], both of which play a role in ischemic preconditioning [18]. Thus even though the signalling systems upstream from the mitochondria appear to differ between TNF{alpha} and ischemic preconditioning, as already argued, they both appear to converge on the mitochondria where the oxygen radicals are thought to be generated [19].

The importance of our findings is that myocardial protection by TNF{alpha} is now well documented, so that a better understanding of the signalling systems involved becomes imperative. The protection in response to exogenous TNF{alpha} is dose-dependent. We have shown that perfusion of TNF{alpha} in an isolated rat heart model at 0.5 ng/ml could mimic ischemic preconditioning and thus, confer cardioprotection. When TNF{alpha} was perfused at a higher or a lower dose than 0.5 ng/ml or if it was perfused without any washout period, the protection against ischemia–reperfusion was lost [6]. Interestingly, the dose of 0.5 ng/ml appears to be very similar to the amount of TNF{alpha} endogenously released in the heart following an ischemia–reperfusion insult. Using the isolated rat heart model, Gurevitch et al. [20] reported that the amount of TNF{alpha} evaluated in the coronary effluents was undetectable in the perfused heart but raised to 752 pmol/ml during the first minute of reperfusion following 1 h of global ischemia. Regarding the role for endogenous TNF{alpha}, we found that TNF{alpha} knockout-mice failed to precondition in response to ischemia [9]. Furthermore, Kurrelmeyer et al. [21] demonstrated that mice deficient in both TNF{alpha} cell surface receptors developed larger myocardial infarcts compared with wild type littermate controls. Thus the suggestion is that this endogenous cytokine is necessary to activate the ischemic preconditioning phenomenon in the intact mouse heart, as also proposed for the development of late preconditioning [22].

The presence of an oxidative stress in the heart is generally associated with an increase in endogenous antioxidant enzymes activities. After TNF{alpha} perfusion, we found an increase of catalase activity while the superoxide dismutase activity remained unchanged. Other studies conducted in the heart have reported an oxidative stress with an activation of catalase and no change in superoxide dismutase [14,23,24]. An explanation for this observation may be a difference in the dynamic and the spatial distribution between these two enzymes.

Free radicals have been suggested as triggers to ischemic preconditioning. Tritto et al. [25] showed that low doses of oxygen radicals could induce preconditioning in the isolated rabbit hearts. Baines et al. [26] reported in situ and in vitro that MPG could abrogate a single episode of preconditioning and proposed that oxygen radicals contribute to ischemic preconditioning via activation of the protein kinase C. In our previous study, we have shown that chelerythrine could abolish TNF{alpha}-induced cardioprotection, also suggesting a role for the protein kinase C in our model of preconditioning with TNF{alpha} [6].

The isolated perfused rat heart preparation was used in our study as this enabled us to demonstrate a protective effect of low doses of TNF{alpha} independent of the known activation of the cytokine cascade following surgical stress in the in vivo preparation. However the perfused heart model does have limitation in that it does not take into account the intracoronary activation of leukocytes which may result in an opposite effect of TNF{alpha} in the setting of myocardial ischemia. Although Kurrelmeyer et al. [21] found that endogenous TNF{alpha} can protect the heart against acute coronary artery occlusion in mice, our findings will be coupled to further in vivo work to more comprehensively evaluate the signalling cascade involved in TNF{alpha}-induced cardioprotection.

In conclusion, our novel data show a central role for free radicals in cardioprotection by TNF{alpha}. Further experiments will be required to determine the source, the localization and the exact role of these free radicals in the cardioprotective effect of TNF{alpha}.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
This study was supported in part by the Circulatory Disorders Research Fund and the Hatter Institute Foundation. We would like to thank Dr Catherine Vergely and Peter Owira for their help in the realisation of this study.


   Notes
 
Time for primary review 30 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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