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CARDIOVASCULAR
Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut (S.D., N.M., D.K.D.); Department of Pharmacology, University of Debrecen, Debrecen, Hungary (S.D., A.T.); and Pharmacy Sciences, Creighton University Medical Center, Omaha, Nebraska (D.B.)
Received for publication
January 29, 2005
Accepted
May 3, 2005.
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Abstract |
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; Hattori et al., 2002; Imamura et al., 2002; Das et al., 2005). The cardioprotective effects of red wine have been attributed to the resveratrol present in red wine (Hung et al., 2004) through diverse mechanisms, including its ability to inhibit low-density lipoprotein (Chen and Pace-Asciak, 1996), block platelet aggregation (Bertelli et al., 1996), and induce NO production (Ma et al., 1993). NO seems to be involved in resveratrol-mediated cardioprotection (Chen and Pace-Asciak, 1996; Hattori et al., 2002; Imamura et al., 2002; Bradamante et al., 2003; Hung et al., 2004), which also plays a crucial role in ischemic preconditioning of the heart (Tosaki et al., 1998; Guo et al., 1999). Several reports exist in the literature to indicate a role of adenosine in resveratrol-mediated preconditioning. Similar to NO, adenosine is also involved in resveratrol preconditioning (Bradamante et al., 2003; Das et al., 2005).
A recent study showed that resveratrol provides cardioprotection through a cyclic AMP response element-binding protein (CREB)-dependent Bcl-2 survival signaling triggered by adenosine A3 receptor activation (Das et al., 2005). This study provides evidence that resveratrol preconditions the heart through the activation of adenosine A1 and A3 receptors, the former transmitting a survival signal through PI3-kinase-Akt-Bcl2 signaling pathway, whereas the latter protects the heart through a CREB-dependent Bcl2 pathway in addition to Akt-Bcl2 pathway.
Adenosine receptor occupancy can lead to the activation of the cAMP-protein kinase A system as well as of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK, all of which can activate the CREB transcription factor system (Chio et al., 2004). Interestingly, p38 MAPK, p42/44 MAPK are also involved in ischemic preconditioning (Ping et al., 1999; Sato et al., 2000). The MAPK pathway is one of the main signal transduction cascades that links extracellular stimuli to proliferation and survival. The upstream signaling component of MAPK, also known as mitogen-activated extracellular signal-regulated protein kinase (MEK), has been found to play a role in the preconditioning process (da Silva et al., 2004). To gain further insight of the adenosine A3 receptor and CREB regulation of resveratrol preconditioning of the heart, we examined the relative contribution of MEK and Akt signaling triggered by adenosine receptor activation. The results of our study revealed that resveratrol potentates an adenosine A3 receptor-mediated CREB-dependent survival signal, which may or may not involve PI3-kinase-Akt pathway.
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Materials and Methods |
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Animals. All animals used in this study received humane care in compliance with the principles of the laboratory animal care formulated by the National Society for Medical Research and The Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication no. 85-23, revised 1985). Sprague-Dawley male rats weighing between 250 and 300 g were fed ad libitum regular rat chow with free access to water until the start of the experimental procedure. The rats were randomly assigned to one of the following groups (Fig. 1): preperfused the isolated hearts for 15 min with Krebs-Henseleit bicarbonate (KHB) buffer containing 1) 0.1% DMSO as a control group, 2) 10 µM resveratrol, 3) 10 µM resveratrol + 1 µM MRS-1191, 4) 10 µM resveratrol + 3 µM LY294002, or 5) 10 µM resveratrol + 20 µM PD098059 or 10 µM resveratrol + 20 µM 098059 + 3 µM LY294002. All hearts were then subjected to 30-min ischemia followed by 2-h reperfusion. Control experiments were performed with vehicle (DMSO) only, MRS-1191 only, LY294002 only, or PD098059 only.
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). At the end of 10 min, after the attainment of steady-state cardiac function, baseline functional parameters were recorded. The circuit was then switched back to the retrograde mode, and the hearts were perfused for 15 min with KHB in the absence or presence of vehicle (control) or various combinations of different drugs as shown in Fig. 1. This was followed by a 5-min washout with KHB buffer, and then the hearts were subjected to global ischemia for 30 min and 2 h of reperfusion. The first 10 min of reperfusion was in the retrograde mode to allow for postischemic stabilization, and thereafter in the antegrade working mode to allow for assessment of functional parameters, which were recorded at 10-, 30-, 60-, and 120-min reperfusion.
Cardiac Function Assessment. Aortic pressure was measured using a Gould P23XL pressure transducer (Gould Instrument Systems Inc., Valley View, OH) connected to a side arm of the aortic cannula. The signal was amplified using a Gould 6600 series signal conditioner and monitored on a CORDAT II real-time data acquisition and analysis system (Triton Technologies, San Diego, CA) (Engelman et al., 1995). Heart rate, left ventricular developed pressure (LVDP) (defined as the difference of the maximum systolic and diastolic aortic pressures), and the first derivative of developed pressure (dP/dT) were all derived or calculated from the continuously obtained pressure signal. Aortic flow was measured using a calibrated flowmeter (Gilmont Instrument Inc., Barrington, IL), and coronary flow was measured by timed collection of the coronary effluent dripping from the heart.
Infarct Size Estimation. At the end of reperfusion, a 10% (w/v) solution of triphenyl tetrazolium in phosphate buffer was infused into aortic cannula for 20 min at 37°C (Das et al., 2005). The hearts were excised and stored at -70°C. Sections (0.8 mm) of frozen heart were fixed in 2% paraformaldehyde, placed between two coverslips, and digitally imaged using a Microtek ScanMaker 600z. To quantify the areas of interest in pixels, an NIH Image 5.1 (a public-domain software package) was used. The infarct size was quantified and expressed in pixels.
TUNEL Assay for Assessment of Apoptotic Cell Death. Immunohistochemical detection of apoptotic cells was carried out using TUNEL (Maulik et al., 2000) with APOP TAG kit (Oncor, Gaithersburg, MD). The heart tissues were immediately put in 10% formalin and fixed in an automatic tissue-fixing machine. The tissues were carefully embedded in the molten paraffin in metallic blocks, covered with flexible plastic molds, and kept under freezing plates to allow the paraffin to solidify. The metallic containers were removed, and tissues became embedded in paraffin on the plastic molds. Before analyzing tissues for apoptosis, tissue sections were deparaffinized with xylene and washed in succession with different concentrations of ethanol (95 and 70% absolute). Then, tissues were incubated again with mouse monoclonal antibody recognizing cardiac myosin heavy chain to specifically recognize apoptotic cardiomyocytes. The fluorescence staining was viewed with a confocal laser microscope. The number of apoptotic cells was counted and expressed as a percentage of total myocyte population.
Western Blot Analysis. Left ventricles from the hearts were homogenized in a buffer containing 25 mM Tris-HCl, 25 mM NaCl, 1 mM orthovanadate, 10 mM NaF, 10 mM pyrophosphate, 10 mM okadaic acid, 0.5 mM EDTA, and 1 mM phenylmethylsulfonyl fluoride (Ray et al., 1999). Protein (100 µg) of each heart homogenate was incubated with 1 µg of antibody against the phospho-Akt, CREB, and phosphorylated CREB (p-CREB) (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) for 1 h at 4°C. The immune complexes were precipitated with protein A-Sepharose, immunoprecipitates were separated by SDS-polyacrylamide gel electrophoresis, and immobilized on polyvinylidene difluoride membrane. The membrane was immunoblotted with PY20 to evaluate the phosphorylation of the compounds. The membrane was then stripped and reblotted with specific antibodies against glucose-6-phosphate dehydrogenase, which served as loading control. The resulting blots were digitized, subjected to densitometric scanning using a standard NIH Image program, and normalized against loading control.
Statistical Analysis. The values for myocardial functional parameters, total and infarct volumes and infarct sizes, and cardiomyocyte apoptosis are all expressed as the mean ± S.E.M. Analysis of variance test followed by Bonferroni's correction was first carried out to test for differences between the mean values of all groups. If differences were established, the values of the treated groups were compared with those of the control group by a modified t test. The results were considered significant if p < 0.05.
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Results |
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LY294002 or PD098059 when used with resveratrol, they each partially abolished the cardioprotective effect of resveratrol, which were evidenced from LVDP from R-60 onwards. The decrease is more prominent at R-120 (69.97 ± 11.96 or 61.35 ± 10.05% versus 87.8 ± 1.74 mm Hg, respectively). The same result also evidenced from LVdp/dt R-30 onwards; the decrease is more prominent at R-60 (1908.67 ± 249.55 mm Hg/s and 2114.7 ± 119.29 versus 2843 ± 79.48 mm Hg/s, respectively) and also at R-120 (932.33 ± 207.45 and 877.7 ± 187.27 versus 1391.8 ± 104.7 mm Hg/s, respectively). The cardioprotective effects were abolished when both PD098059 and LY294002 were used together (Table 1).
Effects of Resveratrol on Myocardial Infarct Size. Infarct size (percentage of infarct versus total area at risk) was noticeably reduced in resveratrol group compared with the control (18.17 ± 2.08 versus 33.79 ± 2.74%). When resveratrol was used along with MRS-1191 or PD098,059 or in combination of PD + LY, they prevented the reduction in infarct size observed with resveratrol alone Thus, the infarct size was significantly higher in resveratrol + MRS-1191 groups compared with the resveratrol group is 26.33 ± 2.45%, as shown in the Fig. 2, top. Inhibition of PI3-kinase with LY294002 or MEK with PD098059 also increased the infarct size (24.9 ± 2.3 and 28.2 ± 1.96%, respectively) compared with resveratrol group. The myocardial infarct size was further increased when both PD098059 and LY294002 were used together (30.05 ± 4.9%).
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Effects of Resveratrol and Adenosine Receptors Antagonists on the Expression of Akt and CREB. Resveratrol significantly enhanced the phosphorylation of Akt and CREB, as supported our previous study. As shown in Figs. 3 and 4, phosphorylation of Akt was increased by 10- to 12-fold and CREB by 6- to 7-fold. The resveratrol-mediated induction of Akt and its subsequent phosphorylation were reduced significantly by MRS-1191 and LY294002, but not with PD098059. In contrast, any one of the three blockers inhibited the phosphorylation of CREB. As shown in Fig. 4, LY294002 and PD098059 partially, but MRS-1191 and LY294002 plus PD098059 almost abolished resveratrol-mediated CREB phosphorylation.
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Discussion |
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Several studies, including our own, have indicated the ability of resveratrol to pharmacologically precondition the heart (Hung et al., 2000; Giovannini et al., 2001; Das et al., 2005). Ischemic preconditioning (PC) refers to the paradoxical mechanism by which cyclic episodes of brief reversible ischemia, each followed by another brief period of reperfusion, render the heart tolerant to subsequent ischemic reperfusion injury (Flack et al., 1991; Engelman et al., 1995; Sato et al., 2000). PC is a complex phenomenon, which occurs through multiple interrelated cascades of events. A variety of neurohumoral factors are released during the onset of PC that include among many intracellular mediators, adenosine (Asimakis et al., 1993; De Jonge et al., 2002; Maddock et al., 2002). Both adenosine A1 and A3 receptors have been implicated in PC-mediated cardioprotection (De Jonge et al., 2002; Schulte et al., 2004). The same adenosine has recently been implicated in resveratrol preconditioning (Bradamante et al., 2003). In addition, NO, which is a powerful mediator of PC (De Jonge et al., 2002), is also involved in resveratrol PC (Bradamante et al., 2003; Das et al., 2005). Resveratrol activates both iNOS and endothelial NO synthase, which presumably contributed toward the ability of resveratrol to provide cardioprotection. In a recent study, resveratrol failed to precondition mouse hearts devoid of any copies of iNOS gene, suggesting a crucial role of iNOS in resveratrol PC (Imamura et al., 2002). A study from our laboratory has indicated a role of both A1 and A3 receptors in resveratrol preconditioning, and both use the PI3-kinase-Akt signaling pathway (Das et al., 2005). The resveratrol-mediated increased Akt phosphorylation occurred at Ser478. The increased Akt phosphorylation was blocked by MRS and 8-cyclopentyl-1,3-dimethylxanthine, suggesting the involvement of both A1 and A3 receptor in Akt signaling. Interestingly, LY294002 abolished the cardioprotective effects of resveratrol, indicating PI3-kinase as the upstream signaling molecule for resveratrol PC.
Akt is a critical regulator of PI3-kinase-mediated cell survival (Kuwahara et al., 2000). Many studies have demonstrated in various cell types that constitutive activation of Akt is sufficient to block cell death induced by a variety of apoptotic stimuli (Zhu et al., 2001). Akt is activated by PC as a result of activation of PI3-kinase, leading to the activation of protein kinase C and endothelial NO synthase (Gliki et al., 2002). Several recent studies showed phosphorylation of Akt as a result of adenosine A3 receptor activation. For example, A3 adenosine receptor activation triggered phosphorylation of protein kinase B/Akt and protected rat basophilic leukemia 2H3 mast cells from apoptosis (Gao et al., 2001). Low concentrations of ethanol activate cell survival promoting PI3-kinase/Akt pathway in endothelial cells by an adenosine receptor-dependent mechanism (Liu et al., 2002). In another study, adenosine receptor was found to regulate insulin-induced activation of PI3-kinase/PKB in rat adipocytes (Takasuga et al., 1999).
Protein kinase B or Akt has been recognized as a survival factor by its ability to inhibit apoptosis (Downward, 1998). Akt, a member of serine/threonine kinase family, is a major target of PI3-kinase, which enhances the level of lipid second messenger PI-3,4,5-triphosphate upon stimulation, leading to its binding to pleckstrin homology domain of Akt (Falasca et al., 1998). This results in the translocation of Akt from cytosol to plasma membrane, where it becomes activated by phosphorylation on Thr308 and Ser473. Finally, Akt is detached from the membrane and goes to both cytosol and nucleus where it regulates gene expression by the stimulation of transcription factors, including nuclear factor-
B and CREB (Brunet et al., 2001). Several downstream targets of Akt have been recognized to be apoptosis regulatory molecules, including bcl-2-family member BAD (Yang et al., 2003) and CREB (Shaywitz and Greenberg, 1999). We recently showed that resveratrol could induce the expression of Bcl-2, which was inhibited by A1 and A3 receptor antagonism. In addition, the downstream target molecules of Bcl2, BAD, and CREB were phosphorylated with resveratrol. 8-(3-Chlorostyryl)caffeine and MRS-1191 significantly inhibited the phosphorylation of BAD, indicating that resveratrol-mediated Akt-Bad survival signal was regulated by both A1 and A3 adenosine receptors. PI3-kinase and Akt signaling pathways were also found to play a critical role in the prevention of apoptotic cell death by adenosine A3 receptor activation (Das et al., 2005).
CREB, a major nuclear transcription factor that transduces cAMP activation of gene transcription, is another regulatory downstream target molecule of Akt (Shaywitz and Greenberg, 1999). CREB has been recognized as an important nuclear factor for cell survival. Overexpresson of a dominant negative CREB transgene induced apoptosis in T cells (Barton et al., 1996). A recent study showed that CREB contributed to cell survival in response to growth factor stimulation (Du and Montminy, 1998). Our results showed simultaneous induction of CREB and Bcl2 in response to resveratrol treatment. The promoter region of Bcl2 contains a cAMP-response element site, and the transcription factor CREB has been recognized as a positive regulator of Bcl2 expression. Like nuclear factor-B, CREB is also a target for several signaling pathways mediated by a variety of stimulation. For example, insulin-like growth factor-1-stimulated CREB phosphorylation was decreased by wortmannin, an inhibitor of PI3-kinase, suggesting a role of Akt in CREB activation.
An alternative survival pathway via CREB that may bypass PI3-kinase-Akt signaling has been described previously (Frodin and Gammeltoft, 1999). In this report, CREB phosphorylation was found to occur through the activation of the MAPK pathway via activation of p90rsk. In another study, relaxin activated CREB through an Akt-independent signaling pathway (Zhang et al., 2002). In this case, CREB may be phosphorylated via MEK/MAPK/p90rsk/CREB or cAMP-protein kinase A signaling pathway, or both (Telgmann et al., 1997). In a related study, dopamine induced PI3-kinase-independent activation of Akt in striatal neurons, indicating a new route to CREB phosphorylation (Brami-Cherrier et al., 2002).
In summary, the results of this study demonstrated that resveratrol preconditioning is mediated by adenosine A3 receptors that trigger CREB phosphorylation via both PI3-kinase-Akt and via MEK-CREB pathways. Resveratrol-mediated phosphorylation of Akt and CREB was blocked by MRS-1191, which also abolished cardioprotective abilities of resveratrol, indicating a crucial role of adenosine A3 receptor for resveratrol preconditioning. That LY294002 completely inhibited Akt phosphorylation but partially blocked the phosphorylation of CREB, resulting in partial inhibition of resveratrol's ability to precondition the heart, suggests that PI3-kinase-Akt-CREB signaling pathway is at least partially responsible for the cardioprotection achieved by resveratrol. Partial blockage of CREB phosphorylation and resveratrol-mediated cardioprotection by PD098059 indicates negative role of PI3-kinase/Akt signaling in CREB activation. This receives further support from the finding that LY294002 and PD098059 together abolished the phosphorylation of CREB simultaneously inhibiting resveratrol-mediated cardioprotection. The results indicate that resveratrol preconditions the hearts through adenosine A3 receptor signaling that triggers the phosphorylation of CREB through both Akt-dependent and -independent pathways, leading to cardioprotection.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: CREB, cAMP response-element binding protein; PI3, phosphatidylinositol 3; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated extracellular signal-regulated protein kinase; MRS-1191 (MRS), 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicar-boxylate; PD098,059 (PD), 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; LY294002 (LY), 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; DMSO, dimethyl sulfoxide; KHB, Krebs-Henseleit bicarbonate; LVDP, left ventricular developed pressure; LVdp/dt, maximum first derivatives of developed pressure; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; p-CREB, phosphorylated cAMP response-element binding protein; Res, resveratrol; R, reperfusion; PC, preconditioning; iNOS, inducible nitric-oxide synthase.
Address correspondence to: Dr. Dipak K. Das, Cardiovascular Research Center, University of Connecticut, School of Medicine, Farmington, CT 06030-1110. E-mail: ddas{at}neuron.uchc.edu
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-myosin heavy chain. Results are expressed as means ± S.E.M. *, p < 0.05 versus control; **, p < 0.05 versus ischemia/reperfusion; 
, p < 0.05 versus resveratrol; 
, p < 0.05 versus resveratrol + PD098059 or resveratrol + LY294002.
