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Am J Physiol Heart Circ Physiol 294: H257-H262, 2008. First published November 2, 2007; doi:10.1152/ajpheart.00769.2007
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Coronary effluent from a preconditioned heart activates the JAK-STAT pathway and induces cardioprotection in a donor heart

Lynn C. Huffman,1 Sheryl E. Koch,2 and Karyn L. Butler1,2

1Department of Surgery and 2Institute of Molecular Pharmacology and Biophysics, University of Cincinnati, Cincinnati, Ohio

Submitted 3 July 2007 ; accepted in final form 1 November 2007


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Preconditioning (PC) protects against ischemia-reperfusion (I/R) injury via the activation of the JAK-STAT pathway. We hypothesized that the mediators responsible for PC can be transferred to naive myocardium through the coronary effluent. Langendorff-perfused hearts from male Sprague-Dawley rats were randomized to paired donor/acceptor protocols with or without PC in the presence or absence of the JAK-2 inhibitor AG-490 (n = 6 for each group). Warmed, oxygenated coronary effluent collected during the reperfusion phases of PC (3 cycles of 5 min ischemia and 5 min reperfusion) was administered to acceptor hearts. The hearts were then subjected to 30 min ischemia and 40 min reperfusion. The left ventricles were analyzed for phosphorylated (p)STAT-1, pSTAT-3, Bax, Bcl, Bcl-XL/Bcl-2-associated protein (BAD), and caspase-3 expression by Western blot. A separate group of hearts (n = 6) was analyzed for STAT activation immediately after the transfer of the PC effluent (no I-R). Baseline cardiodynamics were not different among the groups. End-reperfusion maximal change in pressure over time (+dP/dtmax) was significantly (P < 0.05) improved in acceptor PC (3,637 ± 199 mmHg/s) and donor PC (4,304 ± 347 mmHg/s) hearts over non-PC donor (2,020 ± 363 mmHg/s) and acceptor (2,624 ± 345 mmHg/s) hearts. Similar differences were seen for minimal change in pressure over time (–dP/dtmin). STAT-3 activation was significantly increased in donor and acceptor PC hearts compared with non-PC hearts. Conversely, pSTAT-1 and Bax expression was decreased in donor and acceptor PC hearts compared with non-PC hearts. No differences in Bcl, BAD, or caspase-3 expression were observed. Treatment with AG-490 attenuated the recovery of ±dP/dt in acceptor PC hearts and significantly reduced pSTAT-3 expression. The PC coronary effluent activates JAK-STAT signaling, limits apoptosis, and protects myocardial performance from I/R injury.

apoptosis; cardiac ischemia; ischemia-reperfusion injury; signal transducers and activators of transcription-3

ISCHEMIC PRECONDITIONING (IPC) initiates a powerful endogenous strategy of cellular adaptation to ischemia-reperfusion (I-R) challenge. Translating this phenomenon into a clinically useful tool may protect the myocardium from potential injury in a variety of settings including acute myocardial infarction, cardiac revascularization surgery, supply/demand imbalance in congestive heart failure, and I/R challenge following shock. Factors such as the variability of animal models and experimental protocols and the clinical impact of patient comorbidity have hindered clinical translation (2). It is unlikely that a "silver bullet" will be identified to support at-risk myocardium. However, further advances into understanding the mechanisms of cellular adaptation and identifying potential mediators may yield effective therapeutic strategies with minimal deleterious effects on myocardial performance.

Dickson and colleagues (7) reported a method of preconditioning (PC) by the transfer of the coronary effluent in a rabbit model of global I/R. The mean infarct size in the donor and acceptor PC groups were reduced; however, adenosine or norepinephrine (suspected potential mediators) in the transferred coronary effluent were not detected. Other studies of PC triggers applied to noncardiac vascular beds resulting in cardioprotection have also been described (8, 16). Despite these interesting applications of classical PC, it is unclear whether transferable protection is mediated by signaling pathways or mediators currently known to be effective in classic PC.

Our laboratory (4) and others (15, 18) have reported that the Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is essential for IPC. The cytokine interleukin-6 (IL-6) activates the JAK-STAT pathway and is produced by the heart in response to myocardial I/R challenge (10, 12). Dawn et al. (6) demonstrated that STAT-3 activation (phosphorylation) was significantly reduced in IL-6-depleted mice. IPC, when compared with wild-type controls undergoing similar I/R protocols, did not reduce infarct size in the IL-6-depleted animals. These studies implicate a cardioprotective role for JAK-STAT signaling.

Accordingly, we designed experiments to determine 1) whether PC in the rat heart is transferable to naive (nonischemic) myocardium via the coronary effluent and 2) whether this cardioprotection is mediated by the JAK-STAT pathway or an activator of this pathway. We demonstrate that the coronary effluent released from a PC heart can convey remote protection via the activation of the JAK-STAT pathway in a naive heart subsequently exposed to I/R.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
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All animal protocols followed in this study conformed to the Guide for the Care and Use of Laboratory Animals [National Institutes of Health (NIH) Publication No. 85-23, Revised 1996] and were approved by the Institutional Animal Care and Use Committee of the University of Cincinnati. The animals were provided a standard rat-chow diet and water ad libitum.

Ex vivo cardiac perfusion. Male Sprague-Dawley rats (Harlan, Indianapolis, IN) were anesthetized (90 mg/kg ketamine and 10 mg/kg xylazine) and heparinized (500 units) via intraperitoneal injection. The hearts were rapidly excised and arrested in an iced, oxygenated (95% O2-5% CO2) buffer, mounted on a Langendorff apparatus, and perfused with a Krebs-Henseleit buffer containing (in mmol/l) 10 glucose, 118 NaCl, 2.5 CaCl2, 4.7 KCl, and 25.0 NaHCO3 (pH 7.4) in a nonrecirculating mode at a constant pressure (90 mmHg), as previously described (3). All hearts were mounted and perfused within 40 s of removal from the animal. The Langendorff system was modified to allow the administration of the donor coronary venous effluent (~300 ml) to acceptor hearts at a constant pressure without deterioration in performance or contamination of the main system with donor effluent. This modification consisted of a separate apparatus integrated into the main Langendorff system to permit rapid conversion during the donor effluent administration. The volume of 300 ml was based on the mean coronary flow determined at baseline (20 ml/min) collected during the three reperfusion phases (5 min/phase) of the IPC protocol. A water-filled latex balloon connected to a pressure transducer (AD Instruments) was inserted into the left ventricle through an incision in the left atrium. The pressure transducer was coupled to a Powerlab 4SP (AD Instruments) data recording system. Left ventricular end-diastolic pressure was set at 6–8 mmHg, and the volume of the balloon was left unchanged during the experiment. The hearts were equilibrated for 10 min before any intervention. Hearts that could not achieve a minimal developed pressure of 85 mmHg at the end of the equilibration period were discarded. After global ischemia, all hearts (donor and acceptor) were reperfused on the main Langendorff apparatus. The preparation controls were established by randomizing (coin flip) hearts to I/R on the main system or by 15-min buffer perfusion on the parallel system followed by I/R on the main system (n = 6 in each group).

Experimental protocols. After equilibration, the hearts were randomized to paired donor/acceptor (n = 6 each) I/R protocols (Fig. 1). The donor effluent was warmed (37°C), oxygenated, and then delivered to acceptor hearts over 15 min. Group 1 hearts, the control group, were perfused for 15 min to collect the coronary effluent (donor-control effluent) and then subjected to 30 min of ischemia and 40 min of reperfusion. A separate group of acceptor hearts was perfused on the parallel system with the donor-control effluent and then subjected to I/R challenge. Group 2 donor hearts were preconditioned with IPC (3 cycles of 5 min ischemia and 5 min reperfusion) and then subjected to I/R challenge. The coronary effluent collected during the reperfusion phases was administered to the acceptor hearts before I/R challenge. Group 3 donor hearts were preconditioned as described above, and the coronary effluent was collected during the reperfusion phases. Acceptor hearts were treated with the JAK-2 inhibitor, AG-490 (10 µM over 20 min), perfused with the PC coronary effluent, and then subjected to I/R challenge (4). To differentiate STAT-3 activation by the PC effluent from the activation as a result of the I/R challenge, Group 4 hearts (n = 12) were treated with either PC or non-PC effluent for 15 min but not subjected to I/R challenge. These hearts were freeze clamped in liquid nitrogen for subsequent analysis by Western blot. Cardiac function was assessed at the end of equilibration and again at end reperfusion by determining the first derivative of developed pressure (±dP/dt; in mmHg/s). Coronary flow was determined by the timed collection of the cardiac effluent.


Figure 1
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  		Fig. 1. Donor/acceptor (ACC) experimental groups. PC, preconditioning; I, ischemia; I/R, ischemia- reperfusion.

 
Myocardial STAT expression. At the completion of the perfusion experiments, the hearts were immediately frozen in liquid nitrogen and stored at –80°C until analysis. Preparation of nuclear extracts to identify the phosphorylated (activated) and translocated STAT protein was performed using NXTRACT (Sigma-Aldrich, St. Louis, MO) according to the manufacturer's recommendations with the addition of phosphatase inhibitors containing (in mM) 200 imidazole, 100 NaFl, 115 sodium molybdate, 100 sodium orthovanadate, and 400 sodium tartrate dihydrate (comparable with Phosphatase Inhibitor Cocktail Set II; Calbiochem, La Jolla, CA). Total protein concentrations were determined using the BCA Protein Assay Kit (Pierce, Rockford, IL).

Aliquots of nuclear fractions, corresponding to 100 µg of protein, were separated by 10% SDS-PAGE gel (Gene Mate Express gels; ISC Bioexpress, Salt Lake City, UT), transferred to nitrocellulose membranes (Bio-Rad, Hercules, CA), blocked with 5% bovine serum albumin-Tris-buffered saline (TBS)-Tween, and analyzed with a primary polyclonal antibody against phosphorylated (p)STAT-1 (1:600; Chemicon, Temecula, CA) and primary monoclonal antibodies against pSTAT-3 on tyrosine residue-705 (1:200; Santa Cruz Biotechnology, Santa Cruz, CA). The same immunoblots were stripped and reprobed with a primary polyclonal antibody against total STAT-1 (1:200; Santa Cruz Biotechnology) and total STAT-3 (1:1,000; Chemicon). To normalize protein loading, the membranes were cut and the lower molecular weight portion was analyzed with the primary antibody for GAPDH (1:2,500; Santa Cruz Biotechnology). The arbitrary units on the histograms were derived from dividing the densitometry values (Alpha Ease) determined for the specific proteins by their respective GAPDH densitometry values. Immunoreactive signals were visualized with chemiluminescence luminal reagents (ECL; Amersham Pharmacia Biotech, Piscataway, NJ).

Myocardial apoptotic protein expression. To determine the expression of apoptosis-modulating proteins by Western blot analysis, a protocol modified from Prabhu et al. (17) was used on hearts previously frozen in liquid nitrogen and stored at –80°C until analysis. Briefly, left ventricles from the frozen hearts were pulverized in liquid nitrogen. The samples were then homogenized in a lysis buffer containing 100 mM NaCl, 50 mM Tris·HCl (pH 7.4), 0.1% Triton X-100, 1 mM dithiotreitol, protease inhibitor tablet (Roche Applied Science, Indianapolis, IN), and phosphatase inhibitors containing (in mM) 200 imidazole, 100 NaFl, 115 sodium molybdate, 100 sodium orthovanadate, and 400 sodium tartrate dihydrate (comparable to Phosphatase Inhibitor Cocktail Set II; Calbiochem). The samples were then centrifuged (13,200 rpm at 4°C) for 10 min, and the supernatant was removed and stored on ice until Western blot analysis. Total protein concentrations were determined using the BCA Protein Assay Kit (Pierce). In a loading buffer containing 240 mM Tris·HCl (pH 6.8), 6% SDS, 30% glycerol, 2.3 M 2-mercaptoethanol, and 0.06% bromophenol blue, 50 µg of the protein sample were boiled for 5 min and then separated on a 12% SDS-PAGE gel (Novex Tris-glycine gels; Invitrogen, Carlsbad, CA). The gels were transferred to nitrocellulose membranes (Bio-Rad), blocked with 5% bovine serum albumin-TBS-Tween, and analyzed with a primary antibody. The following primary antibodies were investigated: Bax (N-20, 1:200; Santa Cruz Biotechnology), Bcl-XL/Bcl-2-associated protein (BAD; BAD p112/p136, 1:1,000; Cell Signaling Technology, Danvers, MA), Bcl-2 (DC21, 1:200; Santa Cruz Biotechnology), and caspase-3 (8G10, 1:1,000; Cell Signaling Technology). To normalize protein loading, the membranes were stripped and analyzed with the primary antibody for GAPDH as described in Myocardial STAT expression. Immunoreactive signals were visualized with chemiluminescence luminal reagents (ECL; Amersham Pharmacia Biotech).

Statistical analysis. The data are expressed as means ± SE. The statistical analysis was performed by a two-tailed t-test or one-way ANOVA with Tukey's post hoc analysis for multiple comparisons. P < 0.05 was considered significant.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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Baseline cardiodynamics. Baseline cardiodynamics were obtained after equilibration. Acceptor hearts exhibited a difference only in left ventricular pressure (198 ± 7 vs. 180 ± 4 mmHg, donor vs. acceptor; P = 0.03) compared with donor hearts. Coronary flow, end-diastolic pressure, and maximal and minimal change in pressure over time (+dP/dtmax and –dP/dtmin, respectively) were not significantly different among groups (Table 1).


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  		Table 1. Baseline cardiodynamics

 
Transfer of cardioprotection via coronary effluent. End-reperfusion cardiodynamics are detailed in Table 2. The transfer of PC coronary effluent to acceptor hearts resulted in significantly improved recovery of +dP/dtmax and –dP/dtmin at end reperfusion compared with non-PC donor or non-PC acceptor hearts. Furthermore, there was no difference in end-reperfusion ±dP/dt between donor PC and acceptor PC hearts (Fig. 2). Developed pressure (in mmHg) was monitored throughout the experimental protocol for all groups (Fig. 3). Donor PC and acceptor PC groups exhibited improved myocardial performance throughout reperfusion compared with non-PC hearts, and this protection was abrogated by treatment with AG-490. These results demonstrate the efficacy of the transferred coronary effluent to induce cardioprotection as well as the importance of JAK-STAT signaling in modulating the protection.


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  		Table 2. End-reperfusion cardiodynamics

 

Figure 2
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  		Fig. 2. End-reperfusion myocardial performance in donor/ACC hearts subjected to PC and I/R. PC in donor and ACC hearts resulted in improved post-I/R contractility and relaxation compared with non-PC hearts. JAK-2 inhibition with AG-490 (AG) attenuated this protection. *P < 0.05 vs. donor no PC, ACC no PC, and ACC PC + AG; ^P < 0.05 vs. donor no PC, ACC no PC, and ACC PC + AG; **P < 0.05 vs. donor PC, ACC PC, and ACC no PC. dP/dtmax, maximal change in pressure over time; –dP/dt, minimal change in pressure over time.

 

Figure 3
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  		Fig. 3. Developed pressure (DP) throughout experimental protocols. Recovery of DP was similar in donor PC and ACC PC hearts and significantly improved over that seen in donor no PC and receptor no PC hearts. AG attenuated the protection induced by ischemic PC and transferred PC coronary effluent. *P < 0.05 vs. ACC no PC, donor no PC, and ACC PC + AG.

 
Activation of the JAK-STAT pathway. At the completion of the I/R protocols, nuclear fractions revealed increased pSTAT-3 in PC hearts compared with non-PC controls (Fig. 4A); total STAT-3 was not different between groups. After the administration of PC effluent, in the absence of the I/R challenge, the expression of pSTAT-3 was increased compared with acceptor hearts receiving the non-PC coronary effluent. This suggests that the activation/phosphorylation of STAT-3 is induced by the coronary effluent and not the I/R challenge. The pretreatment of acceptor hearts with AG-490, before infusion of the PC effluent, significantly reduced the expression of pSTAT-3 compared with PC hearts without the inhibitor (Fig. 4B). The reduced pSTAT-3 expression correlated with impaired cardiac performance. There were no differences in the expression of total STAT-1; however, pSTAT-1 expression was significantly decreased in acceptor PC hearts compared with acceptor controls (Fig. 5A). Similarly, Bax expression was also decreased in PC acceptor hearts (Fig. 5B). Both pSTAT-1 and Bax expression correlated inversely with myocardial performance. There were no differences in the expression of BAD, Bcl-2, or caspase-3.


Figure 4
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  		Fig. 4. Representative immunoblot of STAT-3 expression in hearts subjected to I/R, PC, and JAK-2 inhibition. A: phosphorylated (p)STAT-3 expression is significantly increased in donor and ACC PC hearts compared with non-PC hearts. B: pSTAT-3 expression is increased even in the absence of I/R, and this expression is attenuated with JAK-2 inhibition by AG. No differences in total (t)STAT-3 were observed. *P < 0.05 vs. ACC PC ± I/R.

 

Figure 5
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  		Fig. 5. Representative immunoblot of STAT-1 and Bax expression in the presence or absence of PC. A: pSTAT-1 expression is increased in non-PC ACC hearts compared with ACC PC hearts. Donor PC served as a positive (Pos) control. There were no differences in tSTAT-1 expression. B: expression of proapoptotic Bax is similarly increased in non-PC hearts compared with PC hearts. Donor PC serves as a positive control. *P < 0.05 vs. ACC no PC.

 

   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study demonstrates that effective PC can be induced in naive rat myocardium without exposure to ischemic stress. This protection is associated with increased STAT-3 phosphorylation, reduced phosphorylation of STAT-1, and decreased expression of the proapoptotic protein Bax. Furthermore, the protection of contractile function induced by the PC coronary effluent was abrogated in the presence of JAK-2 inhibition. These results implicate an important role for the JAK-STAT pathway in the observed transferred cardioprotection.

Over the past two decades, hundreds of studies have explored mechanisms of classic PC originally described by Murry et al. (14). Few studies, however, have characterized the phenomenon of transferred protection, although variations of classic PC including postconditioning, remote PC, and delayed and late PC have been reported (11, 16). These techniques of protection are similar in that each is accomplished in the target animal model; that is, the triggers inducing protection occur in the animal sustaining the index I/R challenge. Transferring protection, via the PC coronary effluent, suggests that this cytoprotective strategy is mediated by a soluble molecular entity released from the affected myocardium. Our finding of STAT-3 phosphorylation immediately after the transfer of the PC coronary effluent supports the premise that a mediator released into the coronary effluent activates JAK-STAT signaling.

Dickson et al. (7) reported infarct reduction in rabbits treated with PC coronary effluent before the extended I/R challenge. Myocardial performance, however, was not different among the groups. Furthermore, the analysis of the coronary effluent for adenosine and norepinephrine (potential mediators) showed reduced norepinephrine levels and no difference in adenosine content in the PC effluent compared with the control. In our rat model, STAT-3 activation (phosphorylation) correlated directly with functional protection and occurred in the absence of myocardial ischemia in the acceptor hearts. These results confirm the transfer of protection and identify a signaling pathway necessary for effective protection against I/R contractile dysfunction.

Previous studies have characterized a proapoptotic effect of STAT-1 by the upregulation of caspase-1 and proapoptotic genes such as FAS, FAS ligand, p21, and p53 (5, 13). Moreover, Hattori et al. (9) showed the downregulation of proapoptotic genes with IPC in an isolated rat heart preparation but did not correlate STAT-1 activation and myocardial performance. The present study shows that impaired myocardial performance is associated with increased STAT-1 activation. Moreover, the decreased expression of the proapoptotic protein Bax was associated with improved myocardial contractility following PC. Our results suggest that while STAT-3 activation exerts a cytoprotective signal, STAT-1 activation may limit the recovery of contractile function following the I/R challenge possibly as a result of its proapoptotic effect. Our data are consistent with other investigations that suggest a balance between pro- and antiapoptotic factors is necessary for effective cardioprotection (1).

Summary. This is the first study, to our knowledge, that implicates the JAK-STAT pathway in the transfer of cardioprotection. Cardiac PC is a complex phenomenon that likely involves cross talk among various intracellular signaling pathways and balance between cytoprotective and injurious factors. The pharmacomodulation of mediators and/or pathways that maintain this balance may represent a favorable approach to the clinical translation of experimental cardioprotection.

The JAK-STAT pathway represents a unique opportunity to harness endogenous cytoprotective mechanisms. Further studies investigating the efficacy of PC in genetically altered animal models may lend important mechanistic insights into the role of this pathway and its impact on myocardial tolerance to ischemia.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
This work was supported by NIH Grant K-08 HL-68867 (to K. L. Butler). L. Huffman was supported by NIH Training Grant T32-GM-008478, JS-PI.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. L. Butler, Univ. of Cincinnati, Dept. of Surgery, Div. of Trauma/Critical Care, Inst. of Molecular Pharmacology and Biophysics, 231 Albert B. Sabin Way, Cincinnati, OH 45267-0828 (e-mail: Karyn.butler{at}uc.edu)

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.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 

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