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CARDIOVASCULAR

The Cardioprotective Effects of Preconditioning with Endotoxin, but Not Ischemia, Are Abolished by a Peroxisome Proliferator-Activated Receptor- Antagonist

Centre for Experimental Medicine, Nephrology & Critical Care, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary—University of London, Charterhouse Square, London, United Kingdom

Received for publication November 11, 2004
Accepted February 18, 2005.

	Abstract

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We investigated whether endogenous ligands of peroxisome proliferator-activated receptor- (PPAR-) protect the heart against ischemia-reperfusion (I/R) injury. The selective PPAR- antagonist GW9662 (2-chloro-5-nitrobenzanilide) was used in rat models of 1) regional myocardial I/R, 2) ischemic preconditioning, and 3) delayed cardioprotection by endotoxin. We also investigated the effects of the selective cyclooxygenase-2 inhibitor, parecoxib, on ischemic preconditioning and delayed cardioprotective effects of endotoxin. Male Wistar rats were anesthetized with sodium thiopentone. Animals were subjected to either 15 or 25 min of regional myocardial I/R and pretreated with the PPAR- agonist ciglitazone (0.3 mg/kg), the PPAR- antagonist GW9662 (1 mg/kg), or GW9662 and ciglitazone. Animals were also subjected to either 1) ischemic preconditioning alone, ischemic preconditioning, and pretreated with either GW9662 or parecoxib (20 mg/kg) or 2) lipopolysaccharide (LPS) (1 mg/kg) alone, LPS, and pretreated with ciglitazone, GW9662, or parecoxib (20 mg/kg). Myocardial infarct size was determined by p-nitroblue tetrazolium staining. The PPAR- antagonist GW9662 (1 mg/kg) abolished the cardioprotection afforded by the potent PPAR- agonist ciglitazone (0.3 mg/kg). Neither GW9662 nor parecoxib affected the cardioprotective effects of ischemic preconditioning. Pretreatment with ciglitazone did not provide additional cardioprotection to LPS-treated animals. Both GW9662 and parecoxib abolished the delayed cardioprotective effects of endotoxin. Thus, we propose that 1) endogenous ligands of PPAR- are being generated by myocardial ischemia in sufficient amounts to attenuate myocardial I/R injury, and 2) that cyclooxygenase-2 metabolites contribute to (or even account for) the cardioprotective effects of endotoxin (second window of protection) by acting as endogenous PPAR- ligands.

The recent development of a novel class of insulin-sensitizing drugs, the thiazolidinediones (TZDs), represents a new pharmacological class of oral antidiabetic agents. There is good evidence that the beneficial effects of TZDs are due to the activation of PPAR- (Spiegelman, 1998). For instance, the synthetic TZDs were the first class of compounds to be identified as PPAR- ligands (Lehmann et al., 1997). Rosiglitazone and ciglitazone are potent and selective ligands of PPAR- (Lehmann et al., 1997; Young et al., 1998), and there is a good correlation between the potency of the TZDs as PPAR- agonists in vitro and their efficacy at lowering glucose levels in vivo (Willson et al., 2000). In the last few years, we (Thiemermann and Wayman, 2001; Wayman et al., 2002) and others (Yue et al., 2001; Ito et al., 2003; Liu et al., 2004) reported that rosiglitazone, ciglitazone, and pioglitazone reduced the myocardial injury (infarct size) and inflammation caused by regional myocardial ischemia and reperfusion (I/R) in the rat and rabbit. This raises important questions as to whether I/R itself or preconditioning of the heart with endotoxin (delayed) results in the formation of endogenous PPAR- ligands in amounts sufficient to limit the consequences of the ischemic insult. The cyclopentone prostaglandin 15-deoxy-^12,14-PGJ₂ (15d-PGJ₂), which is a metabolite of the prostaglandin D₂, has been suggested to function as an endogenous ligand with a high affinity for PPAR- (Bishop-Bailey, 2000). Most notably, 15d-PGJ₂ protects the heart and other organs against I/R injury (Wayman et al., 2002; Collin and Thiemermann, 2003). The (enzymatic?) source of this endogenous, anti-inflammatory PPAR- ligand is not clear. There is now good evidence that metabolites of cyclooxygenase-2 play important roles in the initiation and the resolution of inflammation. For instance, Gilroy and colleagues have recently provided convincing evidence (in a 48-h rat model of carrageenin-induced pleurisy) that cyclooxygenase-2 may play a key role in the resolution of inflammation by generating anti-inflammatory prostaglandins. The results from this study showed that the first 2 h of the inflammatory response was closely associated with an increase in both the expression of cyclooxygenase-2 and prostaglandin E₂ synthesis. At 48 h, there was a second increase in cyclooxygenase-2 expression. Interestingly, this increase coincided with the increase in the formation of prostaglandin D₂ and 15d-PGJ_2, but was not associated with a substantial increase in prostaglandin E₂ synthesis. Based on these findings, the authors postulated that cyclooxygenase-2 may be proinflammatory during the early phase of carrageenin-induced pleurisy, but anti-inflammatory during the resolution phase of this inflammatory response (Gilroy et al., 1999).

2-Chloro-5-nitrobenzanilide (GW9662) is a specific PPAR- antagonist with a nanomolar IC_50. GW9662 inhibits the activation of the nuclear receptor in an irreversible fashion by causing a covalent modification of a cysteine residue in the ligand-binding pocket of the PPAR- receptor (Leesnitzer et al., 2002). GW9662 inhibits the PPAR--mediated suppression by interleukin-4 of osteoclast formation (Bendixen et al., 2001). GW9662 also abolishes the inhibition of osteoprotegerin gene expression in human aortic smooth muscle cells afforded by PPAR- activation (Fu et al., 2002). GW9662 exacerbates the organ injury caused by hemorrhage and resuscitation, the pathophysiology of which contains an element of I/R injury (Collin et al., 2004). Thus, we hypothesized that endogenous PPAR- ligands may protect the heart against injury caused by I/R. Having demonstrated that GW9662 abolishes the cardioprotective effects of ciglitazone, we have subsequently carried out an extensive investigation designed to elucidate the effects of the specific PPAR- ligand GW9662 in rat models of 1) regional myocardial ischemia and reperfusion (acute ischemic injury), 2) ischemic preconditioning (acute cardioprotection caused by short cycles of ischemia and reperfusion), and 3) delayed cardioprotection with endotoxin (second window of protection caused by lipopolysaccharide; LPS). Finally, we have investigated whether cyclooxygenase-2-derived arachidonic acid metabolites play a role in the delayed cardioprotection afforded by LPS.

	Materials and Methods

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The experiments described in this article were performed in adherence to National Institutes of Health guidelines on the use of experimental animals. All experiments were performed in adherence with the Home Office Guidance on the Operation of the Animals (Scientific Procedures) Act 1986, published by HMSO, London.

This study was carried out on 116 male Wistar rats (Charles River, Margate, Kent, UK) weighing 250 to 320 g receiving a standard diet and water ad libitum. Animals were anesthetized with thiopentone sodium (Intraval 120 mg/kg i.p.). Anesthesia was maintained by supplementary injections of thiopentone sodium as required. The trachea was cannulated, and the animals were ventilated with a Harvard ventilator (inspiratory oxygen concentration: 30%; 70 strokes/min, tidal volume: 8–10 ml/kg). Body temperature was maintained at 37 ± 1°C with the aid of a rectal probe thermometer attached to a homeothermic blanket unit (Harvard Apparatus Ltd., Edenbridge, Kent, UK). The right carotid artery was cannulated and connected to a pressure transducer (Senso-Nor 840; Senso-Nor, Horten, Norway) to monitor mean arterial pressure (MAP) and heart rate (HR), which was displayed on a data acquisition system (MacLab 8e; ADI Instruments, Hastings, UK) installed on a Dell Dimension 4100. The right jugular vein was then cannulated for the administration of drugs. A parasternal thoracotomy was then performed, using an electrosurgery device to cauterize the intercostal arteries before cutting through three ribs. The chest was retracted and pericardium dissected from the heart. The left anterior descending (LAD) coronary artery was isolated and a snare occluder was placed around the LAD. The retractor was then removed, and the animal was allowed to stabilize for 15 min.

Ischemia and Reperfusion. The occluder was tightened at time 0. After either 15 or 25 min of LAD occlusion, the occluder was released to allow reperfusion of the previously ischemic myocardium (2 h). Hemodynamic parameters were continuously monitored. Baseline readings were taken prior to treatment and myocardial ischemia. The pressure rate index, a relative indicator of myocardial oxygen consumption (Baller et al., 1980), was calculated as a product of the MAP and HR and expressed in mm Hg/min x 10³. Saline was administered immediately after reperfusion and throughout reperfusion at a rate of 1 ml/kg/h.

Experimental Design. Due to the extensive nature of this study, the protocols of the five experimental groups have been displayed in Table 1.

Quantification of Myocardial Tissue Injury. At the end of the 2-h reperfusion period, the LAD was reoccluded, and 1 ml of Evans blue dye (2% w/v) was injected into the animal, via the jugular vein. The Evans blue dye stains the tissue through which it is able to circulate so that the nonperfused vascular (occluded) tissue remains uncolored. Each animal was killed with an overdose of anesthetic, the heart excised, and excess dye washed off. The heart was then sectioned into slices of 3 to 4 mm, the right ventricle wall was removed, and the area at risk (AAR—the nonperfused and, hence, nonstained myocardium) was separated from the nonischemic (blue) tissue. The ischemic and nonischemic tissue was weighed, and the AAR was expressed as a percentage of the left ventricle. The tissue from the AAR was cut into small pieces and incubated with p-nitroblue tetrazolium (0.5 mg/ml) for 30 min at 37°C. p-Nitroblue tetrazolium is a reducing agent that reacts with dehydrogenases present in viable (noninfarcted) tissue to produce a dark blue formazan (Nachlas and Shnitka, 1963). Infarcted tissue (nonviable) will not possess dehydrogenase activity and will therefore fail to stain. The stained tissue was separated from the infarcted tissue, weighed, and the infarct size expressed as a percentage of the AAR.

Materials. GW9662 and ciglitazone were obtained from Alexis (Nottingham, UK). Thiopentone sodium (Intraval Sodium) was obtained from Rhône Mérieux Ltd. (Harlow, Essex, UK). Parecoxib was obtained from Sequoia Research Products Limited (Oxford, Oxon, UK). All stock solutions were prepared in nonpyrogenic saline (0.9% NaCl; Baxter Healthcare Ltd., Thetford, Norfolk, UK). Unless otherwise stated, all other compounds were obtained from Sigma-Aldrich Co. (Poole, Dorset, UK).

Statistical Evaluation. All data are expressed as a mean ± standard error of the mean (S.E.M.) of n observations, where n represents the number of animals in the group. Hemodynamic parameters were analyzed via a two-way analysis of variance followed by a Bonferroni post test. AAR and infarct size was analyzed via a one-factorial analysis of variance followed by a Bonferroni post test for multiple comparisons. A P value of less than 0.05 denotes a statistical significant difference when compared with the MI vehicle.

	Results

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Baseline values of MAP, heart rate, and pressure rate index were not significantly different between groups. There was no significant difference in AAR between groups. When compared with sham-operated animals, 15 or 25 min of LAD occlusion followed by 2 h of reperfusion did not cause significant alterations in MAP, heart rate, or pressure rate index. When compared with their respective controls, neither preconditioning nor administration of ciglitazone, GW9662, parecoxib, or LPS (alone or in combination) had any significant effect on MAP, HR, or pressure rate index.

The Cardioprotective Effects of Ciglitazone Are Abolished by a Specific PPAR- Antagonist (Study 1). The mean values for the AAR were similar in all animal groups studied and ranged from 46 ± 2% to 51 ± 3% (Table 2). When compared with sham-operated animals, 25 min of LAD occlusion followed by 2 h of reperfusion caused a significant increase in infarct size (Fig. 1). When compared with vehicle (10% DMSO), administration of ciglitazone (0.3 mg/kg) 30 min prior to the onset of myocardial ischemia caused a significant reduction (by 23%) in myocardial infarct size (Fig. 1). The specific PPAR- antagonist GW9662 (1 mg/kg) abolished the protective effect afforded by ciglitazone (Fig. 1) indicating that the cardioprotective effects of ciglitazone are solely due to activation of PPAR-.

View larger version (25K): [in this window] [in a new window]   Fig. 1. Infarct size in rats subjected to 1) the surgical procedure alone, no LAD coronary artery occlusion and pretreated with 10% DMSO (Sham Vehicle, n = 5) or 2) LAD coronary artery occlusion (25 min) and reperfusion (2 h) and pretreated with either 10% DMSO (MI Vehicle, n = 8), ciglitazone (MI Cig, n = 6), or GW9662 + ciglitazone (MI GW9662 + Cig, n = 5). *, P < 0.05 when compared with MI Vehicle or +, P < 0.05 when compared with MI Cig.

The Specific PPAR- Antagonist GW9662 Augments the Myocardial Infarct Size Caused by Regional Myocardial Ischemia Followed by Reperfusion (Study 2). The mean values for the AAR were similar in all animal groups studied and ranged from 48 ± 2% to 49 ± 1% (Table 2). When compared with sham-operated animals, 15 min of LAD occlusion followed by 2 h of reperfusion caused a significant increase in infarct size. Administration of GW9662 (1 mg/kg), 15 min prior to LAD occlusion, resulted in a further significant increase in infarct size when compared with vehicle-treated animals (10% DMSO) (Fig. 2). Thus, endogenous PPAR- ligands protect the heart against the tissue injury caused by regional myocardial I/R.

View larger version (32K): [in this window] [in a new window]   Fig. 2. Infarct size in rats subjected to 1) the surgical procedure alone, no LAD coronary artery occlusion and pretreated with 10% DMSO (Sham Vehicle, n = 5) or 2) LAD coronary artery occlusion (15 min) and reperfusion (2 h) and pretreated with either 10% DMSO (MI Vehicle, n = 9) or GW9662 (MI GW9662, n = 8). *, P < 0.05 when compared with MI Vehicle.

The Cardioprotective Effects of Ischemic Preconditioning Are Not Affected by the Specific PPAR- Antagonist GW9662 or the Cyclooxygenase-2 Inhibitor Parecoxib (Study 3). The mean values for the AAR were similar in all animal groups studied and ranged from 47 ± 4% to 52 ± 3% (Table 2). When compared with vehicle-treated animals (10% DMSO), two cycles of preconditioning with ischemia resulted in a significant reduction in infarct size by approximately 59% (Fig. 3). Administration of GW9662 (1 mg/kg) or parecoxib (20 mg/kg) did not affect the cardioprotective effect afforded by ischemic preconditioning in the rat heart (Fig. 3).

View larger version (23K): [in this window] [in a new window]   Fig. 3. Infarct size in rats subjected to 1) the surgical procedure alone, no LAD coronary artery occlusion and pretreated with 10% DMSO (Sham Vehicle, n = 5) or 2) LAD coronary artery occlusion (25 min) and reperfusion (2 h) and pretreated with either 10% DMSO (MI Vehicle, n = 9) or two cycles of preconditioning followed by LAD coronary artery occlusion (25 min) and reperfusion (2 h) and pretreated with either 10% DMSO (Precond Vehicle, n = 9), GW9662 (MI GW9662 + Precond, n = 7), or parecoxib (MI Parecoxib + Precond, n = 5). *, P < 0.05 when compared with MI Vehicle.

The Cardioprotective Effects of Endotoxin (Second Window of Protection) Are Abolished by the Specific PPAR- Antagonist GW9662 (Study 4). The mean values for the AAR were similar in all animal groups studied and ranged from 47 ± 2% to 56 ± 2% (Table 2). When compared with vehicle-treated animals (saline), pretreatment with LPS (1 mg/kg i.p.) 16 h prior to the onset of LAD occlusion resulted in a significant reduction in myocardial infarct size by approximately 38%. Interestingly, the specific PPAR- antagonist GW9662 (1 mg/kg) attenuated the cardioprotective effect afforded by LPS (Fig. 4), indicating that the cardioprotective effects of LPS are mediated by endogenous ligand(s) of PPAR-.

View larger version (39K): [in this window] [in a new window]   Fig. 4. Infarct size in rats subjected to 1) the surgical procedure alone, no LAD coronary artery occlusion and pretreated with 10% DMSO (Sham Vehicle, n = 5) or 2) LAD coronary artery occlusion (25 min) and reperfusion (2 h) and pretreated with either saline (MI Vehicle, n = 7), lipopolysaccharide (MI LPS, n = 13), ciglitazone and lipopolysaccharide (MI Cig + LPS, n = 6), GW9662 and lipopolysaccharide (MI GW9662 + LPS, n = 8), or parecoxib and lipopolysaccharide (MI Parecoxib + LPS, n = 6). *, P < 0.05 when compared with MI Vehicle or +, P < 0.05 when compared with MI LPS.

The Cardioprotective Effects of Endotoxin (Second Window of Protection) Are Not Potentiated by PPAR- Agonist Ciglitazone (Study 4). The mean values for the AAR were similar in all animal groups studied and ranged from 47 ± 2% to 56 ± 2% (Table 2). When compared with vehicle-treated animals (saline), pretreatment with LPS (1 mg/kg i.p.) 16 h prior to the onset of LAD occlusion resulted in a significant reduction in myocardial infarct size by approximately 38%. When compared with LPS-treated animals, the pretreatment of ciglitazone (0.3 mg/kg) did not have any additional cardioprotective effect.

The Cardioprotective Effects of Endotoxin (Second Window of Protection) Are Abolished by the Specific Cyclooxygenase-2 Inhibitor (Study 4). The i.v. injectable, selective cyclooxygenase-2 inhibitor parecoxib (Padi et al., 2004) was used to evaluate the role of cyclooxygenase-2 and its metabolites in the cardioprotective effects afforded by LPS. In this study, the mean values for the AAR were similar in all animal groups studied and ranged from 47 ± 2% to 56 ± 2% (Table 2). When compared with vehicle-treated animals (saline), pretreatment with LPS (1 mg/kg i.p.) 16 h prior to the onset of LAD occlusion resulted in a significant reduction in myocardial infarct size by approximately 38%. Interestingly, the specific cyclooxygenase-2 inhibitor parecoxib (20 mg/kg) abolished the cardioprotective effect afforded by LPS (Fig. 4).

	Discussion

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There is now good evidence that a number of chemically distinct agonists of PPAR- including the insulin-sensitizer drugs rosiglitazone, pioglitazone, and ciglitazone and the endogenous cyclopentenone prostaglandins PGA₁ and 15d-PGJ₂ reduce myocardial infarct size in the rat (Thiemermann and Wayman, 2001; Yue Tl et al., 2001; Wayman et al., 2002). Although a number of endogenous PPAR- ligands including 15d-PGJ₂ are known (Bishop-Bailey, 2000; Leesnitzer et al., 2002), it is not clear whether these compounds are being produced during myocardial I/R and if so, whether the amounts produced are sufficient to protect the heart against ischemic I/R injury.

This study demonstrates for the first time that endogenous ligands of the nuclear receptor PPAR- protect the heart (of the rat) against I/R injury. This conclusion is supported by the following specific findings: the specific PPAR- antagonist GW9662 (Leesnitzer et al., 2002) abolished the cardioprotective effects of the specific PPAR- ligand ciglitazone, demonstrating that 1) the cardioprotective effects of ciglitazone are solely due to activation of PPAR- and 2) that GW9662 does indeed function as a specific PPAR- antagonist in the rat heart. We subsequently demonstrate that GW9662 causes a small, but significant, increase in the infarct size caused by short periods (15 min) of myocardial ischemia followed by reperfusion (2 h) in the rat. This finding demonstrates for the first time that endogenous ligands of PPAR- are being produced in sufficient amounts to protect the heart against the injury caused by I/R. Having discovered that endogenous PPAR- ligands are endogenous mediators which protect the heart against I/R injury, we then investigated whether such endogenous PPAR- ligands may contribute to the potent cardioprotective effects caused by preconditioning of the heart with short cycles of regional ischemia (two cycles of 5 min). Although we were able to demonstrate a very substantial reduction in infarct size caused by ischemic preconditioning, pretreatment of rats with the specific PPAR- antagonist GW9662 or the cyclooxygenase-2 inhibitor parecoxib (15 min prior to ischemic preconditioning) did not affect the cardioprotective effects of ischemic preconditioning. Thus, cyclooxygenase-2 metabolites or PPAR- ligands are very unlikely to contribute to the cardioprotective effects of ' ischemic preconditioning.

There is also good evidence that pretreatment of animals with cell-wall fragments of either Gram negative (endotoxin, LPS) or Gram positive (lipoteichoic acid, LTA) bacteria reduce the degree of myocardial tissue injury (and infarct size) caused by LAD occlusion and reperfusion at 8 to 24 h after injection of small amounts (1 mg/kg) of LPS or LTA (Brown et al., 1989; Rowland et al., 1996; Zacharowski et al., 2000). We confirm here that LPS (1 mg/kg i.p.) causes a significant reduction in the infarct size following LAD occlusion (25 min) and reperfusion (2 h) at 16 h after the administration of LPS. The mechanism(s) underlying these potent cardioprotective effects of LPS (or LTA) are not clear. We report here for the first time that the specific PPAR- antagonist GW9662 (1 mg/kg i.p. at 30 min prior to and 8 h after LPS) largely attenuated the cardioprotective effects of LPS in the rat. These findings demonstrate that the delayed cardioprotective effects afforded by LPS in the rat are largely due to endogenous PPAR- agonists. Pretreatment of ciglitazone (1 mg/kg i.p. at 30 min prior to and 8 h after LPS) did not produce any additional cardioprotective effects. Taken together, these results indicate that the delayed cardioprotective effects of LPS are due to endogenous PPAR- agonists.

There is a large body of evidence to suggest that 15d-PGJ_2, a dehydration product of prostaglandin D₂ which in turn is a derivative of prostaglandin H₂, is a potent PPAR- agonist (Bishop-Bailey, 2000). Under physiological conditions, however, 15d-PGJ₂ is not produced in sufficient amounts to activate PPAR- (Bell-Parikh et al., 2003). However, it appears that larger amounts of endogenous PPAR- agonists are being produced during the resolution phase of inflammation (Gilroy et al., 1999). Thus, we propose that the induction of cyclooxygenase-2 will lead to the generation of cyclooxygenase-2-derived eicosanoids, which serve as endogenous ligands for PPAR-. This hypothesis is strongly supported by our finding that the selective cyclooxygenase-2 inhibitor parecoxib abolished the delayed cardioprotective effects of LPS in the rat.

Although cyclooxygenase-2 has been implicated in many inflammatory disorders, Gilroy and colleagues have used a 48-h model of carrageenin-induced pleurisy to suggest that cyclooxygenase-2 has anti-inflammatory properties. They have suggested that there is a switch in prostaglandin synthesis from proinflammatory prostaglandins at the onset of inflammation to anti-inflammatory prostaglandins at the resolution of inflammation (Gilroy et al., 1999). We have previously reported that pretreatment of rats with LPS at 8 to 24 h prior to the onset of regional myocardial I/R protects the heart against I/R injury. However, LPS pretreatment 2 to 4 h prior to myocardial I/R did not attenuate myocardial I/R injury (Zacharowski et al., 2000). Thus, we used a 16-h LPS pretreatment protocol in this experiment. Based on the findings of Gilroy and colleagues and our own previous findings (Zacharowski et al., 2000), we propose that the induction of cyclooxygenase-2 (by LPS) in the heart results (after 4–8 h) in the formation of anti-inflammatory prostaglandins, which serve as endogenous PPAR- ligands and protect the heart against I/R injury.

In conclusion, this study demonstrates for the first time that the delayed (second window of protection) cardioprotective effects of LPS, but not those of acute ischemic preconditioning, are at least in part due to the generation of cyclooxygenase-2-derived eicosanoids, which serve as endogenous ligands of PPAR-. These findings imply that inhibition of the activity of cyclooxygenase-2 abolishes the formation of endogenous, cardioprotective PPAR- ligands, which in turn impairs the ability of the heart to protect itself against the consequences of I/R injury.

	Footnotes

 
A.S. and this work was supported by a Ph.D. Studentship from the William Harvey Research Foundation.

doi:10.1124/jpet.104.080598.

ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; TZD, thiazolidinedione; I/R, ischemia and reperfusion; 15d-PGJ₂, 15-deoxy-^12,14-prostaglandin J₂; GW9662, 2-chloro-5-nitrobenzanilide; LPS, lipopolysaccharide; MAP, mean arterial pressure; HR, heart rate; LAD, left anterior descending; AAR, area at risk; MI, myocardial infarction; DMSO, dimethyl sulfoxide; LTA, lipoteichoic acid.

Address correspondence to: Professor C. Thiemermann, Centre for Experimental Medicine, Nephrology and Critical Care, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary—University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom. E-mail: c.thiemermann{at}qmul.ac.uk

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