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1 School of Biomedical and Natural Sciences, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK
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Abstract |
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(Received 12 April 2005;
accepted after revision 16 June 2005; first published online 17 June 2005)
Corresponding author J. M. Dickenson: School of Biomedical and Natural Sciences, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK. Email: john.dickenson{at}ntu.ac.uk
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Introduction |
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Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase B (PKB; also known as Akt) cascades are important signalling pathways which mediate cell survival and cardioprotection (Armstrong, 2004). For example, Yue et al. (2000) have shown that ERK1/2 inhibition using the MEK1/2 inhibitor, PD 98059, potentiated reperfusion injury in perfused rat hearts. Similarly, ERK1/2 is reportedly involved in the development of delayed preconditioning induced by sublethal simulated ischaemia/reperfusion (I/R) in rat neonatal cardiomyocytes (Punn et al. 2000). More recent studies have revealed enhanced I/R injury in vivo in Erk2+/– heterologous gene-targeted mice (Lips et al. 2004). There is also increasing evidence that PKB protects myocardium from I/R-mediated injury. The PI3-kinase inhibitors, LY 294002 and wortmannin, inhibited functional recovery induced by ischaemic preconditioning in perfused rat heart (Tong et al. 2000). Similarly, these inhibitors reversed ischaemic preconditioning-reduced infarct size in perfused rat and rabbit hearts (Baines et al. 1999; Mocanu et al. 2002). Finally, adenoviral-mediated expression of constitutively active PKB protects against I/R-induced injury in mouse and rat hearts (Matsui et al. 1999, 2001; Fujio et al. 2000).
At present the involvement of ERK1/2 and PI3-kinase/PKB in adenosine receptor-mediated cardioprotection is poorly understood. Previous studies have shown that adenosine-induced preconditioning in isolated rabbit hearts is not blocked by the PI3-kinase inhibitor wortmannin (Qin et al. 2003). Similarly, in transgenic mice over-expressing the A1 adenosine receptor, cardioprotection against I/R-induced apoptosis does not appear to involve PI3-kinase (Regan et al. 2003). More recently, the non-selective A1/A2A/A3 adenosine receptor agonist NECA has been shown to reduce reperfusion-induced infarction in rabbit hearts via PI3-kinase and ERK1/2 (Yang et al. 2004). Our own studies have recently shown that PI3-kinase-dependent pathways do not appear to be involved in adenosine-induced preconditioning in rat neonatal cardiomyocytes (Germack et al. 2004). The aim of the present study was to investigate the role of ERK1/2 and PI3-kinase/PKB in adenosine receptor-induced cardioprotection using isolated rat right ventricular strips, contracted by electrical-field stimulation, as a model system. Our results indicate that pharmacological cardioprotection with selective A1, A2A and A3 adenosine receptor agonists protects against hypoxia-induced reduction in isolated rat right ventricular strips. However, pretreatment of ventricle strips with the MEK1 inhibitor PD 98059 or the PI3-kinase inhibitor wortmannin had no significant effect on cardioprotection induced by selective A1, A2A and A3 adenosine receptor agonists. These observations suggest that ERK1/2 and PI3-kinase/PKB-dependent pathways are not involved in adenosine receptor-mediated preconditioning in isolated rat ventricular strips.
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Methods |
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All experiments were conducted on adult Wistar rats (175–400 g body weight). Rats were killed by cervical dislocation in accordance with the Animals (Scientific Procedures) Act 1986. Hearts were rapidly excised and immediately placed into ice-cold heart Krebs solution (mM): 119 NaCl, 25 NaHCO3, 11.1 D-glucose, 4.7 KCl, 2.5 CaCl2, 1.2 KH2PO4 and 1.0 MgSO4. Right ventricle strips were isolated (one per heart), placed in Krebs solution, mounted between platinum electrodes and isometric force transducers under 2 g tension and paced at a frequency of 1 Hz. All strips were equilibrated at 37°C in Krebs buffer gassed with 95% O2–5% CO2 for 40 min prior to experimentation. Hypoxic conditions were simulated by replacing the medium with glucose-free Krebs solution gassed with 95% N2–5% CO2 at 37°C.
Experimental protocols
Control ventricle strips were exposed to 30 min oxygenation followed by 30 min hypoxia and then reoxygenation for 30 min. Hypoxic preconditioning involved a 10 min exposure to hypoxia followed by 20 reoxygenation prior to 30 min hypoxia followed by reoxygenation for 30 min. Where appropriate the selective adenosine receptor agonists CPA (A1 receptor), CGS 21680 (A2A receptor) and Cl-IB-MECA (A3 receptor) were added 2 min before (and then agonist-containing medium removed and replaced with glucose-free Krebs solution gassed with 95% N2–5% CO2 at 37°C) to 30 min hypoxia followed by reoxygenation for 30 min. Adenosine receptor antagonists (DPCPX (A1), ZM 241385 (A2A), MRS 1220 (A3)) were added 28 min before the adenosine receptor agonists (both removed before 30 min hypoxia). Similarly, PD 98059 (a cell-permeable and reversible MEK1 inhibitor and wortmannin (a cell-permeable and irreversible PI3-kinase inhibitor) were added 30 min before hypoxic preconditioning or treatment with the adenosine receptor agonists and removed before 30 min hypoxia. The experimental protocols are summarized in Fig. 1.
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All data are presented as means ± S.E.M. The n in the text refers to the number of separate experiments. All data are presented as percentage contraction recovery, which represents the level by which the ventricle strips regain contractile function following the 30 min hypoxic episode. Statistical significance was determined by one-way analysis of variance (ANOVA) followed by a Bonferroni test. P < 0.05 was considered statistically significant.
Materials
Bovine serum albumin, adenosine, CPA (N6-cyclopentyladenosine), DPCPX 1,3-dipropylcyclo-pentylxanthine and theophylline were obtained from Sigma (Poole, UK). PD 98059 (2'-amino-3'-methoxy-flavone) and wortmannin were purchased from Calbiochem (Nottingham, UK). CGS 21680 (4-[2-[[-6-amino-9-(N-ethyl-ß-D-ribofuranuronamidosyl)-9H-purin-2-yl]-amino]ethyl]benzenepropanoic acid), 2-Cl-IB-MECA (1-[2-chloro-6[[(3-iodophenyl)-methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-ß-D-ribofuranuronamide), ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5ylamino]ethyl)phenol) and MRS 1220 (N-[9-chloro-2-(2-furanyl)[1,2,4]-triazolo[1,5-c]quinazolin-5-yl]benzene acetamide) were from Tocris (Bristol, UK). All other chemicals were of analytical grade.
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Results |
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The primary aim of this study was to investigate the role of ERK1/2 and PI3-kinase/PKB-dependent pathways in adenosine receptor-mediated pharmacological preconditioning using isolated rat ventricle strips. In agreement with previous studies hypoxic preconditioning (10 min hypoxia followed by 20 min reoxygenation) significantly enhanced contractile recovery seen after 30 min hypoxia followed by reoxygenation for 30 min (see Fig. 2; Cerruti et al. 2002). Similarly, application of 10 µM adenosine 2 min before exposure to hypoxia (30 min) significantly improved posthypoxia contraction (Fig. 2). In order to assess which adenosine receptor subtype(s) mediate pharmacological preconditioning in rat ventricle strips we used CPA (1 µM), CGS 21680 (1 µM) and Cl-IB-MECA (100 nM), selective A1, A2A and A3 adenosine receptor agonists, respectively. As shown in Fig. 2 all three agonists significantly improved contraction recovery to a similar extent to that induced by hypoxic preconditioning and adenosine. The selective adenosine receptor antagonists DPCPX (A1; 10 µM), ZM 241385 (A2A; 1 µM) and MRS 1220 (A3; 1 µM) attenuated the cardioprotective effects mediated by CPA, CGS 21680 and Cl-IB-MECA, respectively (Fig. 3). Overall, these data indicate that A1, A2A and A3 adenosine receptors trigger pharmacological preconditioning in rat ventricle strips.
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The role of ERK1/2 and PI3-kinase in A1, A2A or A3 adenosine receptor-mediated preconditioning was explored using the pharmacological inhibitors PD 98059 and wortmannin, selective inhibitors of MEK1 (upstream activator of ERK1/2) and PI3-kinase, respectively. As shown in Fig. 4, pretreatment with PD 98059 (50 µM) and wortmannin (100 nM) significantly inhibited the contraction recovery induced by hypoxic preconditioning (Fig. 4A). However, PD 98059 and wortmannin had no significant effect on pharmacological preconditioning mediated by CPA, CGS 21680 or Cl-IB-MECA (Fig. 4B–D). Importantly, pretreatment with wortmannin or PD 98059 alone had no significant effect on the contraction recovery in control strips exposed to 30 min hypoxia (Fig. 4E). Overall these results appear to indicate that ERK1/2 and PI3-kinase are not involved in A1, A2A or A3 adenosine receptor-induced cardioprotection in rat ventricle strips. However, both ERK1/2 and PI3-kinase are implicated in hypoxic preconditioning.
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Discussion |
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In this study we also explored which adenosine receptor subtypes induce preconditioning using a range of selective agonists. In agreement with numerous previous studies using in vivo models of reperfusion injury, isolated heart preparations and cardiomyocytes in culture, activation of the A1 adenosine receptor, using the selective agonist CPA, induced cardioprotection in rat ventricle strips. Similarly, the A3 adenosine receptor agonist Cl-IB-MECA also protected rat ventricle strips from hypoxia-induced loss of contractile function. These data are in agreement with previous studies, which have reported A3 adenosine receptor-mediated cardioprotection in rat hearts and newborn rat cardiomyocytes (Maddock et al. 2002; Germack & Dickenson, 2005).
The involvement of the A2A adenosine receptor in cardioprotection is controversial. Several groups using in vivo models of reperfusion injury have reported protective effects of the selective A2A adenosine receptor agonist CGS 21680 (Norton et al. 1992; Schlack et al. 1993). The in vivo reduction in reperfusion injury induced by CGS 21680 is thought to involve A2A adenosine receptor-mediated inhibition of neutrophil accumulation and superoxide generation (Jordon et al. 1997). The beneficial effects of CGS 21680 have also been observed using neutrophil-free isolated perfused rat heart preparations, suggesting that additional mechanisms are involved in A2A adenosine receptor-mediated cardioprotection (Lozza et al. 1997). However, Maddock et al. (2002) observed that CGS 21680 added at reperfusion did not reduce infarct size in isolated rat heart. Similarly, our own studies have shown that CGS 21680 does not prevent hypoxia–reoxygenation-induced lactate dehydrogenase (LDH) release from isolated rat cardiomyocytes (Germack & Dickenson, 2005). However, in this study we have shown that CGS 21680 protected rat ventricle strips from hypoxia-induced loss of contractile function. Furthermore, the selective A2A adenosine receptor antagonist, ZM 241385, attenuated the protective effects of CGS 21680. Possible explanations for these contradictory results include the use of different model systems and, in the case of Maddock et al. (2002), the A2A adenosine receptor agonist was added at reperfusion. In addition, in this study we have only assessed contractile function and not cellular damage, so it is conceivable that the effects observed with CGS 21680 (and possibly adenosine) may relate to the enhancement of posthypoxia contractility via increases in intracellular cAMP levels and not via the modulation of cellular death (Lasley et al. 2001). Clearly, further studies are required in order to clarify the involvement of the A2A adenosine receptor in cardioprotection.
As outlined in the Introduction, the primary aim of this study was to investigate the role of ERK1/2 and PI3-kinase in adenosine receptor-induced preconditioning using rat ventricle strips. For comparison we also assessed whether ERK1/2 and/or PI3-kinase are involved in hypoxic preconditioning. As shown in Fig. 4A, the PI3-kinase inhibitor wortmannin significantly reduced functional recovery induced by hypoxic preconditioning in rat ventricle strips. These data are in agreement with previous studies, which have also shown that wortmannin inhibits ischaemic preconditioning in perfused rat and rabbit hearts (Baines et al. 1999; Tong et al. 2000; Mocanu et al. 2002). In contrast, the role of ERK1/2 in classical or early preconditioning is controversial. For example, although several groups have reported effective inhibition of ischaemic preconditioning using PD 98059 in neonatal rat cardiomyocytes and perfused rat hearts (Punn et al. 2000; Fryer et al. 2001), other data suggest that ERK1/2 is not involved in ischaemic preconditioning of rabbit (Kim et al. 1999), pig (Behrends et al. 2000) or rat heart (Mocanu et al. 2002). However, as shown in Fig. 4A, PD 98059 (50 µM) inhibited the contraction recovery induced by hypoxic preconditioning in rat ventricle strips. The variations in the data surrounding the involvement of ERK1/2 in ischaemic preconditioning may again relate to species differences, model systems (cells versus isolated hearts) or end-points monitored.
Although ERK1/2 and PI3-kinase are involved in hypoxic preconditioning they do not appear to be involved in A1, A2A and A3 adenosine receptor-induced cardioprotection in rat ventricle strips since PD 98059 and wortmannin had no significant effect on pharmacological preconditioning mediated by CPA, CGS 21680 and Cl-IB-MECA (see Fig. 4B–D).
At present it is not entirely clear why hypoxic preconditioning is sensitive to PD 98059 and wortmannin, whereas pharmacological preconditioning with CPA, CGS 21680 and Cl-IB-MECA appears to be independent of ERK1/2 and PI3-kinase. However, the results do suggest that hypoxic preconditioning and pharmacological preconditioning with adenosine receptor agonists appear to involve the activation of different signalling pathways in rat ventricle strips. Indeed, previous studies have shown that cardioprotection induced by ischaemic preconditioning and the mitochondrial KATP channel opener diazoxide are dependent upon reactive oxygen species (ROS), whereas CCPA- (adenosine A1 receptor agonist) mediated preconditioning is independent of ROS (Hausenloy et al. 2004). Similarly, protection induced by adenosine and its analogue, N6-(2-phenylisopropyl) adenosine, were insensitive to the free radical scavenger, N-2-mercaptopropionyl glycine (MPG), and the mitochondrial KATP channel blocker, 5-hydroxydecanoate (5-HD). In contrast, bradykinin-, morphine- and phenylephrine-induced cardioprotection were blocked by MPG and 5-HD (Cohen et al. 2001). These observations clearly indicate that classical ischaemic preconditioning and pharmacological preconditioning induced by bradykinin, morphine and phenylephrine involve different signalling pathways compared to cardioprotection triggered by adenosine receptor activation.
It is important to note that differences in adenosine versus ischaemic preconditioning and pharmacological preconditioning induced by bradykinin, morphine and phenylephrine may relate to adenosine catabolism via xanthine oxidase-generating ROS (Gelpi et al. 2002). However, in the present study the use of specific adenosine receptor agonists would seem to eliminate this possibility. It also possible that the differing sensitivity of hypoxic preconditioning versus pharmacological preconditioning (with adenosine receptor agonists) to inhibitors of ERK1/2 and PI3-kinase may reflect the slightly different protocols employed. The hypoxic preconditioning protocol included a 20 min recovery period before prolonged hypoxia whereas the 2 min pharmacological preconditioning with adenosine receptor agonists did not include a recovery period. The data obtained with the PI3-kinase inhibitor wortmannin are in agreement with previous studies reporting that adenosine-induced preconditioning in isolated rabbit hearts is not blocked by wortmannin (Qin et al. 2003). Similarly, using isolated rat neonatal cardiomyocytes exposed to simulated hypoxia and reoxygenation, we have recently shown that protective effects mediated by A1 and A3 adenosine receptor agonists (inhibition of caspase 3 activation and LDH release) are not blocked by wortmannin (Germack & Dickenson, 2005). Overall, these observations suggest that PI3-kinase-dependent signalling pathways are not involved in the early phases of A1 and A3 adenosine receptor-mediated cardioprotection. However, further studies are required in order to explore the possible role of PI3-kinase in A1 and A3 adenosine receptor-induced delayed preconditioning.
The data presented in this study suggest that ERK1/2 is not involved in A1, A2A and A3 adenosine receptor-mediated cardioprotection in rat ventricle strips. It is important to note that A1, A2A and A3 adenosine receptors are functionally expressed in isolated rat cardiomyocytes and activate ERK1/2 (Germack & Dickenson, 2004). It is also noteworthy that previous studies, including work from our group, do suggest that ERK1/2 is involved in adenosine receptor-mediated cardioprotection. For example, the non-selective A1/A2A/A3 adenosine receptor agonist, NECA, has recently been shown to reduce reperfusion-induced infarction in rabbit hearts via ERK1/2 (Yang et al. 2004). Similarly, treatment of isolated neonatal rat cardiomyocytes with PD 98059 blocked A1 and A3 adenosine receptor-mediated cardioprotection (Germack & Dickenson, 2005). The discrepancy between the data presented in this study compared with our previous work reporting the involvement of ERK1/2 in A1 and A3 adenosine receptor-mediated cardioprotection may simply reflect the use of two different model systems. The cardioprotective effects in isolated neonatal rat cardiomyocytes were assessed by monitoring the release of LDH and the activation of caspase 3 (markers of cell damage) following hypoxia and reoxygenation, whereas in this study we have monitored posthypoxia contractile recovery.
In conclusion, we have presented data showing that selective A1, A2A and A3 adenosine receptor agonists promote functional contractile recovery in rat ventricle strips exposed to hypoxia and reoxygenation. Pharmacological inhibitors of MEK1/2 (upstream activator of ERK1/2) and PI3-kinase, PD 98059 and wortmannin, respectively, had no significant effect on A1, A2A and A3 adenosine receptor-induced preconditioning in ventricle strips. However, it is noteworthy that both inhibitors attenuated hypoxic preconditioning in this model system. These observations suggest that different signalling pathways involved are involved in hypoxic preconditioning versus pharmacological preconditioning triggered by selective A1, A2A and A3 adenosine receptor agonists.
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