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Medical College of Wisconsin, Department of Pharmacology and Toxicology, Milwaukee, Wisconsin
Submitted 3 January 2006 ; accepted in final form 23 February 2006
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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(GSK-3) inhibition is mediated by the JAK/STAT pathway. Rats underwent 30 min of ischemia and either 5 min or 2 h of reperfusion, followed by tissue isolation for molecular analysis or infarct size assessment, respectively. Rats were treated with vehicle, morphine (300 µg/kg), the 
-opioid agonist fentanyl isothiocynate (FIT, 10 µg/kg), or the GSK inhibitor SB-216763 (SB21, 600 µg/kg) 10 min before ischemia. Five minutes before opioid or SB21 treatment, some rats received the putative JAK2 inhibitor AG-490 (3 mg/kg) or the putative JAK3 inhibitor ZM-449829 (3 mg/kg). H9C2 cardiomyoblast cells were also used to investigate FIT-induced signaling (1 µM) in vitro via molecular analysis. Morphine induced the phosphorylation of JAK2, yet not JAK1, in the area at risk. Morphine, FIT, and SB21 also reduced infarct size compared with vehicle (water) when administered before ischemia [43.0 ± 2.8, 39.1 ± 3.1, and 42.1 ± 2.5 (*P < 0.001, respectively) vs. 58.1 ± 1.3%, respectively]. AG-490 abrogated OIC, whereas ZM-449829 had no effect on OIC. Cardioprotection was afforded by SB21 even in the presence of AG-490. Morphine phosphorylated STAT3, Akt, and GSK-3, and phosphorylation was abrogated by AG-490. FIT stimulation of H9C2 cells also caused a time-dependent phosphorylation of STAT3, Akt, and GSK-3, and this effect was abrogated by AG-490. STAT3 phosphorylation was also dependent on phosphatidylinositol 3-kinase (PI3K) activation in both tissue and H9C2 cells. These data suggest that OIC occurs via the JAK2 regulation of PI3K pathway-dependent STAT3, Akt, and GSK-3, with GSK-3 contributing a central role in acute OIC.
Janus-activated kinase; glycogen synthase kinase; opioids; morphine; infarct size
Of the four JAK family members, JAK1, JAK2, and TYK2 are present in the heart. JAK3, however, is suggested to be selectively located in T lymphocytes or cells of hematopoietic origin (12, 26). The putative JAK2 inhibitor AG-490 abrogated ischemic preconditioning (IPC)-induced acute cardioprotection, with IPC shown to phosphorylate both JAK1 and JAK2 without affecting TYK2 (34). In addition to IPC, growth factors and hormones, including IGF-I, erythropoietin, and angiotensin II, also activate JAK family proteins through phosphorylation (7, 16). Collectively, it appears these agents investigated preferentially activate JAK1 or JAK2 in cardiomyocytes, yet it is unknown whether opioids activate the JAK family, especially JAK1 or JAK2, in the cardiovascular system and mediate acute opioid-induced cardioprotection.
All STAT family members are present in cardiac myocytes (34). STAT isoform-specific knockout or transgenic mice would collectively suggest a role for STAT1, STAT3, and STAT5A in cardioprotection, whereas STAT6 is not involved (7, 8, 11, 21, 24). STAT1 activation appears to enhance myocardial injury, whereas STAT3 activation is protective (8, 22).
It is unknown whether opioids induce acute cardioprotection through the JAK/STAT pathway; however, a previous study indicates that opioids can activate JAK/STAT signaling in human embryonic kidney cells (13). Because opioids were shown to require tyrosine kinases for cardioprotection, perhaps tyrosine phosphorylation of JAK or STAT family members are required for opioid-induced cardioprotection (5). Hence, we determined the significance of the JAK/STAT pathway in opioid-induced cardioprotection. Furthermore, we determined whether this pathway regulates the phosphatidylinositol 3-kinase (PI3K) pathway, including phosphorylation and inactivation of glycogen synthase kinase-3 (GSK-3), which has recently been shown to facilitate acute opioid-induced cardioprotection (6).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Male Sprague-Dawley rats (215–300 g) were obtained from Harlan (Indianapolis, IN) and used for an in vivo anesthetized intact rat model of ischemia and reperfusion. Briefly, thiobutabarbital sodium (Inactin, 100 mg/kg ip) was used to anesthetize the rats, and a tracheotomy was performed, followed by artificial ventilation. The left common carotid artery was cannulated for blood pressure, heart rate, and blood-gas measurements. A fifth intercostal space thoracotomy was performed, the pericardium excised, and a ligature was placed around the area of the left anterior descending coronary artery, near the first diagonal branch. Occlusion of the area at risk (AAR) was performed by placing the two ends of the ligature through a polypropylene tube, fixing the tube to the epicardial surface. The hemostat was removed after 30 min of occlusion, and the AAR was reperfused for 2 h. The ligature was again reoccluded, and the AAR was determined by patent blue negative staining. The left ventricle was excised and cross-sectioned into four to five slices and further separated into the normal zone and AAR. Slices were incubated in 1% 2,3,5-triphenylterazolium chloride to determine infarct size. The heart was incubated overnight in 10% formaldehyde, and the infarcted tissue was dissected from the AAR and measured gravimetrically. Infarct size was expressed as a percentage of the AAR.
Additional animals (n = 4–6 rats/group) in the vehicle, morphine, and AG-490 + morphine groups were euthanized 5 min after reperfusion for molecular analysis, and tissue samples were prepared by homogenizing the tissue, followed by an initial centrifugation (10,000 g for 10 min) to remove cellular debris. The supernatant was again centrifuged at 100,000 g to enrich for the cytosolic fraction. The homogenizing buffer used was previously described (6). Other animals (n = 4 rats/group) also received the PI3K inhibitor wortmannin (15 µg/kg), given 5 min before morphine was administered 10 min before ischemia. Wortmannin has previously been shown to abolish morphine-induced cardioprotection when administered at this dose and time point (6).
The H9C2 cell line, derived from the left ventricle of the embryonic rat heart, was obtained from American Type Culture Collection. Cells were maintained in DMEM containing 5.56 mmol/l glucose, L-glutamine, pyridoxine HCl, and 1 mmol/l sodium pyruvate (Invitrogen) and supplemented with 10% fetal bovine serum, 30 U/ml penicillin, 10 µg/ml streptomycin, and 2 µg/ml fungizone.
Western blot analysis was conducted as previously described (6). Equal loading of samples was confirmed by Ponseau staining. The chemiluminescent signal produced was captured on X-ray film and quantified by using NIH image 1.62. For tissue studies, samples were run on one to two gels for each antibody, and the background was standardized. The raw density value measured by NIH image 1.62 was reported. For H9C2 studies, each time course data set was run on an individual gel and assessed by NIH image 1.62. These data were reported as the percent change in densitometry (from 100%) from the unstimulated cell group.
Pharmacological agents. The agents used for this study included fentanyl isothiocyanate {FIT, N-1-[2-(4-isothiocyanatophenyl)ethyl]-4-piperidinyl-N-phenylpropanamide, Tocris}, morphine (Sigma), ZM-449829 (Tocris), AG-490 (Tocris), SB-216763 (SB21, Tocris), and wortmannin (Sigma). FIT was dissolved in 95% ethanol and further diluted 1:100 with water for a final volume of 0.12–0.15 ml. Morphine was dissolved in water. The four other agents were dissolved in DMSO, with the final volume of DMSO between 0.12 and 0.15 ml.
Antibodies.
The primary antibodies used were for JAK1 phospho (P)-Tyr1022/1023, JAK2 P-Tyr1007/1008, STAT1 P-Ser727 and P-Tyr701, STAT3 P-Ser727 and P-Tyr705, and GSK-3 P-Ser9 and Akt P-Ser473. All primary antibodies were purchased from Cell Signaling and diluted 1:1,000 in Tris-buffered saline containing 3% BSA. The secondary antibody used was anti-rabbit, purchased from Bio-Rad and diluted 1:5,000.
Hemodynamics. Hemodynamics, including heart rate, mean arterial pressure, and rate pressure product, were quantified during baseline, 15 min into ischemia, and at 2 h of reperfusion.
JAK involvement in acute opioid-induced cardioprotection. Animals treated with either vehicle or morphine (n = 4 rats/group) were euthanized 5 min after reperfusion, and tissue samples were prepared as described previously to determine whether opioids phosphorylated JAK1 and/or JAK2 (6).
Acute infarct size studies with opioids.
For the acute infarct size studies, morphine (300 µg/kg) or the selective -opioid agonist FIT (10 µg/kg) was administered 10 min before ischemia. Subsets of these groups received either the putative JAK2 inhibitor AG-490 (3 mg/kg) or the putative JAK3 inhibitor ZM-449829 (3 mg/kg) 15 min before ischemia, either before opioid administration or alone.
Acute infarct size with GSK inhibition. An additional series of experiments determined whether the selective GSK inhibitor SB21 (600 µg/kg) can reduce infarct size when administered 10 min before ischemia while in the presence of the putative JAK2 inhibitor AG-490, administered 15 min before ischemia.
H9C2 experiments.
H9C2 cells were grown to 
80% confluence on 60-mm dishes and were then placed in serum-free DMEM for 24 h. Cells were either treated with vehicle (ethanol) or with FIT (1 µmol/l) for times ranging between 1 and 15 min. A further set of H9C2 cells was incubated with either the selective PI3K inhibitor wortmannin (100 nmol/l) or the selective JAK2 inhibitor AG-490 (100 µmol/l) for 40 min, with a subset of these cells receiving FIT (1 µmol/l) for the final 10 min. H9C2 cells were rapidly placed on ice, and the media were removed. Cells were then washed twice in chilled PBS. Lysis buffer was applied to cells, and lysates were centrifuged at 10,000 g for 10 min to remove cellular debris, with 25–30 µg of the supernatant used for Western blot analysis.
Statistical significance. All values were denoted as means ± SE. Statistical significance was determined by performing a one-way ANOVA with Bonferroni's correction for multiplicity, or when only two groups were compared, a two-tailed t-test was performed. A significant difference was indicated by P < 0.001, P < 0.01, or P < 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Opioid-induced JAK phosphorylation at reperfusion. At 5 min of reperfusion, morphine significantly phosphorylated JAK2 compared with that in vehicle-treated rats [186 ± 14 (P < 0.05) vs. 143 ± 11%, densitometry units (DU); Fig. 1]. No differences were found in phosphorylation of JAK1 when comparing morphine-treated to vehicle-treated rats (141 ± 4 vs. 141 ± 3%, DU, respectively; Fig. 1).
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JAK/STAT pathway interactions with PI3K pathway.
Morphine induced the phosphorylation of the PI3K-dependent proteins Akt Ser473 and GSK-3 Ser9 [166 ± 17 (P < 0.01) vs. 116 ± 14, Fig. 4, left; and 173 ± 7 (P < 0.05) vs. 114 ± 9 DU, Fig. 4, right, respectively]. Morphine-induced phosphorylation of Akt and GSK-3 was also abrogated in the presence of AG-490 (85 ± 4, Fig. 4, left; and 110 ± 13 DU, Fig. 4, right, respectively). Furthermore, the morphine-induced phosphorylation of STAT3 at Tyr705 was abrogated in the presence of wortmannin [196 ± 10 (P < 0.01) vs. 143 ± 11 DU, respectively; Fig. 5].
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FIT induced a significant phosphorylation of STAT3 Tyr705 at 5, 10, and 15 min compared with unstimulated cells [122 ± 8, 169 ± 13 (P < 0.01), 161 ± 11 (P < 0.01), and 171 ± 8% (P < 0.01); Fig. 7A]. Phosphorylation of Akt also occurred at 10 and 15 min by FIT [101 ± 2, 104 ± 8, 151 ± 16 (P < 0.05), and 234 ± 15% (P < 0.05); Fig. 7B]. FIT-induced phosphorylation of GSK- also occurred at 10 and 15 min [121 ± 9, 121 ± 11, 147 ± 9 (P < 0.05), and 151 ± 15% (P < 0.05); Fig. 7C].
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that occurred at 10 min after FIT stimulation [147 ± 9 (P < 0.001), 91 ± 5 (P < 0.05), and 56 ± 11%, respectively; Fig. 8B]. Wortmannin, when administered alone, also significantly reduced levels of P-GSK-3 well below unstimulated cells, whereas AG-490 administration alone was not significantly different [45 ± 6 (P < 0.001) and 103 ± 4%, respectively; Fig. 8A]. Both AG-490 and wortmannin abrogated FIT-induced phosphorylation of STAT3 that occurred at 10 min after FIT stimulation [161 ± 11 (P < 0.001), 77 ± 10, and 106 ± 4%, respectively; Fig. 8C]. Wortmannin or AG-490, when administered alone, did not significantly reduce levels of P-STAT3 below unstimulated cells [102 ± 13 and 92 ± 12%, respectively; Fig. 8C].
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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, and STAT3. Furthermore, our data suggest that STAT3 phosphorylation requires PI3K activation, which is parallel with or downstream of JAK2. The ability for the selective GSK inhibitor SB21 to reduce infarct size in the presence of AG-490 indicates that GSK inhibition mediates the protective pathway induced by opioids via JAK2. In H9C2 cells, the -opioid agonist FIT also induced JAK/STAT and PI3K-dependent protein phosphorylation, with AG-490 inhibition resulting in pharmacological inhibition of Akt, GSK-3, and STAT3 phosphorylation by opioids. Previous findings have shown that pharmacological inhibition by AG-490 of JAKs abolishes the acute cardioprotection achieved by IPC (7, 16). However, our study is the first to demonstrate that pharmacological-induced cardioprotection via opioids requires JAK2 to reduce infarct size. The phosphorylation of JAK2, but not JAK1, is different from IPC-induced JAK phosphorylation, which phosphorylates both JAKs (34). Our data also suggest that nonmyocardial sources of JAK3 do not contribute to opioid-induced cardioprotection in the intact rat, because the putative JAK3 inhibitor ZM-449829 failed to abrogate or benefit opioid-induced cardioprotection.
A prior study of opioids would suggest that tyrosine kinase activation is important for cardioprotection because the general tyrosine kinase inhibitor genistein abolished opioid-induced cardioprotection (5). In this respect, the tyrosine phosphorylation of JAK2 may be important for activation of multiple cardioprotective pathways, and this study has shown that opioids induce tyrosine phosphorylation of JAK2.
Previously, besides the contribution of STAT3 in ischemia-reperfusion injury, STAT3 has also been shown to aid in the cardioprotection against doxorubicin-induced cardiomyopathy (11), hypoxia/reoxygenation-induced oxidative stress (17), and cerebral ischemia (33). Because these were acute studies, it suggests that STAT3 activation contributes to the initial stage of cardioprotection, in addition to the more accepted role of regulating protein transcription that is essential for delayed cardioprotection (34). Interestingly, opioids phosphorylated STAT3 at Tyr705 without affecting the phosphorylation of the more proapoptotic STAT1.
An unexpected finding was that opioids failed to reduce the phosphorylation state of STAT1 in addition to STAT3 phosphorylation. A number of studies (23, 24) indicate that apoptotic pathways are triggered via the carboxyl terminal of STAT1 and that phosphorylation at the Ser727 site has been linked to myocyte-induced apoptosis from ischemia-reperfusion. Hence, because opioids do not modify STAT1, opioids may contribute to cardioprotection by shifting the cellular state to the more active STAT3 than STAT1, indicative of an initiation of more anti-apoptotic than proapoptotic pathways.
Our present findings also indicate that cross talk exists between the JAK/STAT and PI3K pathways in the heart. Furthermore, the interaction would indicate that opioid-induced STAT3 phosphorylation via JAK2 requires PI3K. Molecular cross talk between JAK/STAT and PI3K has previously been shown to exist in nonmyocardial cells that are activated by luteinizing hormone or carbon monoxide (3, 36). Lysophosphatidylcholine-induced upregulation of the endothelial nitric oxide synthase promoter was also found to require both JAK2 and PI3K (4). Moreover, phosphorylation of Akt by an active JAK2 was shown to be PI3K dependent (18). Therefore, this interaction appears to be a common pathway that may exist in the cardiovascular and other organ systems between JAK/STAT and PI3K.
The interaction between the JAK/STAT and PI3K pathways may be due to the formation of protein complexes. This is supported by a study where an association between JAK2 and the p85 component of PI3K has been reported (18). Concomitantly, the p85 subunit of PI3K has also been shown to be required for STAT3 phosphorylation in nonmyocardial cells (19). STAT3 may also act as an adaptor molecule for PI3K to interact with opioid receptors, because STAT3 has been previously found to be required to couple to the p85 subunit of PI3K to the interferon surface receptor-1 (19). Hence, these data suggest that STAT3, in addition to its role in nuclear gene transcription, may contribute toward the formation of protein complexes outside the nucleus by serving as an adaptor protein to link two proteins together. In the case of the p85 subunit of PI3K, sequence analysis would suggest the interaction is plausible, because both JAK2 and STAT3 contain a YXXM sequence motif, which was previously shown upon tyrosine phosphorylation to allow docking of the SH2 domain of PI3K (19, 20). Although further experiments will be required, our data suggest that upon opioid receptor-induced JAK2 phosphorylation, STAT3 and PI3K are recruited and interact and cause the inactivation of GSK-3.
Inhibition of GSK-3 has been shown to act as a central mediator of cardioprotection via phosphorylation by proteins, including tyrosine kinases, G protein-coupled receptors, protein kinase A, Akt, target of rapamycin (TOR), PKC, and the ATP-sensitive K+ (KATP) channel (10). Our data would suggest that JAK2 also mediates the inactivation by phosphorylation of GSK-3. The ability for GSK inhibition by SB21 to result in cardioprotection in the presence of AG-490 would suggest that JAK2 is an upstream mediator of GSK-3 inhibition.
Interestingly, GSK-3 inhibition was shown to mediate the cardioprotective effects of IPC, KATP channel openers, opioids, adenosine, and bradykinin by inhibiting the mitochondrial permeability transition pore (10). Therefore, these data suggest that the protection afforded by opioids via JAK2 targets the proteins associated with the mitochondria. This is further supported by preliminary data that suggest IPC-induced cardioprotection by JAK2 transduces the protective signal to the mitochondria to cause cardioprotection (9).
How cardioprotective pathways are mediated by JAK2 via GSK-3 inhibition may stem from interactions with p53. JAK2 has previously been shown to augment cell cycle and apoptosis via p53 (29). Moreover, pharmacological inhibition of p53 results in acute cardioprotection that is PI3K pathway dependent (15). A direct interaction between p53 and GSK-3 has also been reported after DNA damage, and GSK-3 has been shown to activate p53 through phosphorylation (28, 31, 32). Hence, inhibition of GSK-3 would not activate p53, and GSK-3 and p53 in unison would determine cellular fate. This interaction will need to be further explored in detail as a potential mechanism of opioid-induced cardioprotection, because morphine has recently been shown to reduce apoptosis via p53 inhibition (25).
These data should be interpreted within the potential constraints of several limitations. Although opioids did not induce JAK1 phosphorylation in either tissue or cells, IPC-induced phosphorylations of JAK1 and JAK2 were both abrogated by AG-490 in a prior study (34), suggestive that AG-490 may also inhibit JAK1. Additionally, AG-490 has also been reported to partially inhibit JAK3 and the EGF receptor. Hence, we used ZM-449829 as a positive control for AG-490 because this agent is a more selective inhibitor for JAK3 than AG-490 and also inhibits the EGF receptor and JAK1. ZM-449829 was shown not to affect opioid-induced cardioprotection. This suggests that JAK2, which is inhibited only by AG-490, is required for opioid-induced cardioprotection.
Other studies have suggested that a 10-fold lower dose of AG-490 was needed to achieve a JAK2 inhibitory effect than in our present findings (14, 30, 35). However, comparisons between these studies and our study are difficult, because the inhibitory effects of AG-490 are likely dependent on multiple factors, including the length of time AG-490 was applied and signaling pathway variability between the specific cell line, tissue type, or animal species used, in addition to the dosing effects. When compared with previous studies conducted with AG-490 in rat hearts, Negoro et al. (16) reported that AG-490 resulted in an attenuation of myocardial viability as assessed by transferase-mediated dUTP nick-end labeling (TUNEL); however, Xaun et al. (34) reported that AG-490 did not alter infarct size when compared with that of the control group, as in our present study. These finding likely differ due to the reperfusion window used, drug dose, and technique for assessment of myocardial viability. However, our findings also cannot exclude that the dose used may have nonspecific effects.
Because pharmacological inhibitors are not present for STAT3, only a correlation can be shown to exist in these studies between myocardial infarct size and STAT3 phosphorylation. However, the requirement for STAT3 in cardioprotection has been previously shown in STAT3 knockout mice (8). In turn, SB21, the GSK inhibitor used, is a nonselective GSK inhibitor for both the 
- and -isoforms. However, our previous study has shown the cardioprotection afforded by opioids is due to the phosphorylation of GSK-3 and not GSK-3 (6). Furthermore, nuclear extracts were not investigated because any nuclear translocation would likely cause changes in gene transcription, a mechanism not likely to be associated with acute cardioprotection.
For our molecular studies, whether opioids directly activate the signaling pathways, such as the JAK/STAT pathway, or cause a prolonged activation of these pathways during reperfusion requires future study. In addition, the total protein levels of Akt, GSK-3, STAT1, and STAT3 were not altered for the vehicle-treated compared with the morphine-treated groups at 5 min of reperfusion; however, total protein was not assessed for all groups. A previous study would support that total protein levels are unlikely changed 5 min after reperfusion (27). Also, additional methods of assessing cardiac damage, such as DNA laddering or caspase release, or TUNEL expression need further studies to confirm the infarct size data provided.
In summary, opioid-induced cardioprotection occurs via the phosphorylation of JAK2 and STAT3, which, in turn, regulates PI3K-dependent proteins Akt and GSK-3 (Fig. 9).. Pharmacological inhibition of GSK-3 is cardioprotective in the presence of AG-490, further suggesting that GSK-3 is downstream of JAK2 and has a central role in acute opioid-induced cardioprotection.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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P < 0.05, significant difference compared with vehicle.
