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Ann Thorac Surg 2005;80:2235-2241
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

p38 Mitogen Activated Protein Kinase Mediates Both Death Signaling and Functional Depression in the Heart

^a Section of Cardiothoracic Surgery, Departments of Surgery, Indianapolis, Indiana, USA
^b Cellular and Integrative Physiology, Indianapolis, Indiana, USA
^c Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

Accepted for publication May 19, 2005.

^_* Address correspondence to Dr Meldrum, 545 Barnhill Dr, Emerson Hall 215, Indianapolis, IN46202 (Email: dmeldrum{at}iupui.edu).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: Understanding the myocardial inflammatory response to ischemia is an important part of achieving the elusive clinical goal of long-enduring myocardial protection. p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant stress-induced myocardial tumor necrosis factor production. However, it is unknown whether p38 MAPK mediates the following important events in both myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3, and caspase-11 activation, and tumor necrosis factor, interleukin-1ß and interleukin-6 production.

METHODS: Isolated rat hearts were perfused and subjected to an ischemia-reperfusion insult, with and without preischemic infusion of 20µM SB203580 (p38 MAPK inhibitor). Myocardial functional measurements were continuously recorded throughout the experiments. Myocardial tissue was then assessed for products of p38 MAPK activation, expression of tumor necrosis factor, interleukin-1ß and interleukin-6, and activation of caspase-1, caspase-3 and caspase-11.

RESULTS: Postischemic recovery of left ventricular developed pressure, +dP/dt and –dP/dt was significantly increased by p38 MAPK inhibition (MKI) (left ventricular developed pressure: 48.4 ± 3.87 MKI versus 32.7 ± 4.32 mm Hg; +dP/dt: 1392.0 ± 141.7 MKI versus 896.7 ± 128.5 mm Hg/s; –dP/dt: –889.9 ± 97.63 MKI versus –548.9 ± 71.29 mmHg/s). p38 MAPK inhibition also significantly reduced ischemia–reperfusion-induced elevation of left ventricular end-diastolic pressure (82.76 ± 4.59 MKI vs 69.95 ± 3.55 mm Hg). p38 MKI decreased myocardial tumor necrosis factor, interleukin-1ß and interleukin-6 protein levels, and reduced active myocardial caspase-1, caspase-3 and caspase-11.

CONCLUSIONS: The p38 MAPK pathway indeed mediates the following important events in myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3 and caspase-11 activation, and tumor necrosis factor, interleukin-1ß, interleukin-6 production after myocardial ischemia. Single site (p38 MAPK) inhibition of these events may have important therapeutic implications in myocardial protection.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Acute injury in the form of ischemia, endotoxemia, or burn trauma results in myocardial functional suppression, in part by the local production of inflammatory mediators such as tumor necrosis factor (TNF)-, interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) [1–3]. These mediators may be important contributors to postischemic myocardial dysfunction, apoptosis, and hypertrophy. One of the key signaling enzymes involved in myocardial proinflammatory cytokine production and apoptosis is p38 mitogen-activated protein kinase (MAPK) (Fig 1) [4, 5]. Activation of myocardial p38 MAPK after ischemia-reperfusion (I-R) has been observed in animal and human studies [6–8], and inhibition of p38 MAPK activation results in improved myocardial function after I-R injury [9–12]. Although abundant evidence exists regarding the important role of p38 MAPK in signal transduction leading to myocardial apoptosis after I-R injury, little is known about the influence of p38 MAPK on the following important events in myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK₂), caspase-1, caspase-3, and caspase-11 activation, and TNF, IL-1ß, and IL-6 production after myocardial ischemia. The potential therapeutic opportunity to provide single site (eg, p38 MAPK) inhibition of these events may have clinical appeal.

View larger version (27K): [in this window] [in a new window]   Fig 1. The p38 mitogen-activated protein kinase (MAPK) signaling in inflammation and apoptosis. Acute ischemia-reperfusion, oxidant stress, and hydrogen peroxide directly activate p38 MAPK, which results in activation of downstream signal-mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 ). Active p38 MPAK and MAPKAPK2 lead to tumor necrosis factor (TNF) gene induction. Nuclear factor kappa B (NFB) is activated by inhibitory B (IB) phosphorylation and subsequently disruption of the NFB-IB complex. Activated NFB translocates from the cytoplasm to the nucleus, where it docks to the TNF promoter and activates TNF gene transcription. Active p38 MAPK and MAPKAPK2 also result in production of interleukin-1 beta (IL-1ß) by active/cleaved caspase-11 and caspase-1. The inflammatory response (p38 MAPK signaling, TNF, and IL-1ß) and caspase-11 eventually lead to active caspase-3 and apoptosis.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

Isolated Heart Preparation (Langendorff)
Rats were anesthetized (sodium pentobarbital, 60 mg/kg intraperitoneally) and heparinized (500 units intraperitoneally), and hearts were rapidly excised through a median sternotomy and were placed in 4°C Krebs-Henseleit solution. The aorta was cannulated and the heart was perfused (70 mm Hg) with oxygenated (95% O₂ 5% CO₂) Krebs-Henseleit solution (37°C). Composition of Krebs-Henseleit solution was (in mM): 5.5 glucose, 119 NaCl, 1.2 CaCl₂, 4.7 KCl, 25 NaHCO₃, 1.18 KHPO₄, and 1.17 MgSO₄ (Sigma, St. Louis, MO). The perfusion buffer was continuously filtered through a 0.45 microfilter to remove particular contaminants. Analysis of the gassed perfusate revealed pO₂ of 440 to 460 mm Hg, pCO₂ of 39 to 41 mm Hg, and pH of 7.39 to 7.41 (ABL-4 blood gas analyzer, Radiometer, Copenhagen, Denmark). A pulmonary arteriotomy and left atrial resection were performed prior to insertion of a water-filled latex balloon through the left atrium into the left ventricle. The pre-load volume (balloon volume) was held constant during the entire experiment to allow continuous recording of the left ventricular developed pressure and left ventricular end-diastolic pressure (LVEDP). The balloon was adjusted to a mean LVEDP of 5 mm Hg (range, 4 to 8 mm Hg) during the initial equilibration. Pacing wires were fixed to the right atrium, and hearts were paced at approximately 6 Hz, 3 V, 2 ms (350 beats per minute) throughout perfusion. A three-way stopcock above the aortic root was used to create global ischemia, during which the heart was placed in a 37°C degassed organ bath. Data was continuously recorded using a PowerLab 8 preamplifier/digitizer (AD Instruments Inc, Milford, MA) and an Apple G4 Power PC computer (Apple Computer Inc, Cupertino, CA). The maximal positive and negative values of the first derivative of pressure (+dP/dt and dP/dt) were calculated using PowerLab software.

Experimental Groups
Each I-R experiment lasted a total of 80 minutes: 15 minute equilibration period, 25 minutes of global ischemia (37°C), and 40 minutes of reperfusion. The I-R was performed in the presence (I-R + p38 MKI; n = 19) or absence (I-R alone; n = 14) of the p38 MAPK inhibitor SB 203580 (Sigma, St. Louis, MO). SB 203580 (final concentration 20 µM) was prepared daily in Krebs-Henseleit solution and infused through a port above the aortic root (not re-circulated) during the last 5 minutes of the equilibration period and prior to the I-R insult. Control hearts (n = 6) underwent 80 minutes of oxygenated perfusion without any periods of ischemia to ensure preparation stability. At the conclusion of experiments, hearts were removed, sectioned, and snap frozen in liquid nitrogen.

Myocardial TNF, IL-1ß, and IL-6
Heart tissue was homogenized in cold buffer containing 20 mM Tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM ß-glycerophosphate, 1 mM Na3VO4, 1 µg/mL leupeptin, and 1 mM PMSF, and were centrifuged at 12,000 rpm for 5 minutes. Myocardial TNF, IL-1ß (active/cleaved) and IL-6 in the cardiac tissue were determined by enzyme-linked immunosorbent assay using a commercially available enzyme-linked immunosorbent assay set (R&D Systems Inc, Minneapolis, MN and BD Biosciences, San Diego, CA). Enzyme-linked immunosorbent assay was performed according to the manufacturer's instructions.

Western Blotting for p38 MAPK and Apoptosis Proteins
Homogenized heart tissue was subjected to Western immunoblot for measurement of p38 MAPK and cleavage/active caspase-1, caspase-3, and caspase-11. The protein extracts (30 µg/lane) were subjected to electrophoresis on a 12% tris-HCl gel (Bio-Rad, Hercules, CA) and transferred to a nitrocellulose membrane, which was stained by Naphthol blue-black (Bio-Rad) to confirm equal protein loading. The membranes were incubated in 5% dry milk for 1 hour and then incubated with the following primary antibodies: p38 MAP kinase antibody, phosphor-p38 MAP kinase (Thr180/Tyr182) antibody, phosphor-MAPKAPK₂ (Thr334) antibody (Cell Signaling Technology, Beverly, MA), caspase-1 p20 (G-19), caspase-3 (H-277), and caspase-11 (M-20) (Santa Cruz Biotechnology, Santa Cruz, CA), and were followed by incubation with horseradish peroxidase-conjugated goat anti-rabbit and bovine anti-goat IgG secondary antibody and detection using supersignal west pico stable peroxide solution (Pierce, Rockford, IL). Films were scanned using an Epson Perfection 3200 Scanner (Epson America, Long Beach, CA) and band density was analyzed using TotalLab Software (Fotodyne, Hartland, WI).

Presentation of Data and Statistical Analysis
All reported values are mean ± standard error of the mean. Data were compared using two-way analysis of variance (ANOVA) with post-hoc Bonferroni/Dunn test and unpaired t tests. Differences at the 95% confidence level were considered statistically significant.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Myocardial Function
I-R resulted in a marked decrease (p < 0.001) in myocardial function, as demonstrated by a decrease in left ventricular developed pressure (mm Hg) from 103.8 ± 3.73 to 32.7 ± 4.32 and 100.5 ± 2.20 to 48.4 ± 3.87 in I-R alone (n = 14) and I-R + p38 MKI (n = 19) groups, respectively (Fig 2A). Postischemic recovery of left ventricular developed pressure at 30 and 40 minutes of reperfusion in the I-R + p38 MKI group was significantly higher than that in I-R alone group (I-R + p38 MKI: 43.85 ± 3.92 vs I-R alone: 30.31 ± 3.42 at 30 minutes [p <0.01]; I-R + p38 MKI: 49.50 ± 3.87 vs I-R alone: 32.68 ± 4.32 at 40 minutes [p < 0.001]).

View larger version (29K): [in this window] [in a new window]   Fig 2. Changes in myocardial function after ischemia and reperfusion in ischemia/reperfusion (I/R) alone (n = 14) and I/R + p38 mitogen-activated protein kinase inhibitor (MKI) (n = 19) rat hearts perfused with modified Krebs-Henseleit solution. (A) Left ventricular (LV) developed pressure. (B) Left ventricular end-diastolic pressure. (C) The +dP/dt. (D) The –dP/dt. Results are mean ± standard error of the mean. *p < 0.05. **p < 0.01. ***p < 0.001 versus I/R alone at the corresponding points.

The +dP/dt and –dP/dt were impaired at the start of reperfusion (Figs 2C, 2D), but toward the end of the reperfusion period (40 min), the I-R + p38 MKI group had greater improvement in +dP/dt (1,433 ± 144.4 vs I-R alone: 896.7 ± 128.5; p < 0.01) and –dP/dt (–920.6 ± 98.7 vs I-R alone: –549.0 ± 71.3; p < 0.01) compared with the I-R alone group.

p38 MAPK Activation
Activation of p38 MAPK pathway was determined by Western blot assessment of phosphorylated p38 MAPK and its downstream substrate, mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2). Acute ischemia and reperfusion resulted in increased activation of p38 MAPK (phosphorylated-p38 MAPK demonstrated as percentage of total p38) (I-R alone, [n = 6]: 81.5 ± 5.2% vs control [n = 5]: 36.0 ± 10.3%; p < 0.05) and MAPKAPK₂. Figure 3A shows equal total p38 MAPK in all groups, but increased phosphorylation of p38 MAPK and MAPKAPK2 in the I-R alone hearts (81.5 ± 5.2%; n = 6), which were decreased by p38 MAPK inhibition (54.7 ± 14.8%; n = 4). Equal loading of the samples was confirmed by Naphthol blue-black staining.

View larger version (41K): [in this window] [in a new window]   Fig 3. The expression of activated p38 mitogen-activated protein kinase (MAPK) signaling pathway is increased after ischemia/reperfusion (I/R) injury in I/R alone relative to I/R + p38 mitogen-activated protein kinase inhibitor (MKI). (A) Representative immunoblots show nonphosphorylated p38 MAPK (total) in the top row with phosphorylated p38 MAPK (active) in the bottom row. (B) Representative immunoblots show phosphorylated mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 ) (active). (C) Densitometry data of p-p38 MAPK (percentage of total p38 MAPK). (Mean ± standard error of the mean [n = 4 to 6/group].) *p < 0.001 versus control, p < 0.05 versus I/R alone.

View larger version (14K): [in this window] [in a new window]   Fig 4. Ischemia-reperfusion (I/R)-induced production of (A) myocardial tumor necrosis factor (TNF), (B) interleukin-1 beta (IL-1ß), and (C) interleukin-6 (IL-6) protein. Protein levels of myocardial TNF, IL-1ß, and IL-6 were significantly increased by I/R, but p38 mitogen-activated protein kinase inhibitor decreased these myocardial cytokines compared with I/R alone. (Mean ± standard error of the mean [n = 4 to 5/group]). *p < 0.05 versus control; p < 0.05 versus I/R alone.

View larger version (51K): [in this window] [in a new window]   Fig 5. Expression of caspase-1 and caspase-11 in control, ischemia-reperfusion (I/R) alone and I/R + p38 MKI rat hearts after I/R injury. (A) Shown are representative immunoblots of precursor procaspase-11 in the top row with active caspase-11 in the bottom row. (B) Shown are representative immunoblots of precursor procaspase-1 in the top row with active caspase-1 in the bottom row. (C) Densitometry data of caspase-11 (% of procaspase-11). The I/R increased expression of active caspase-11 levels. The increased caspase-11 activation after I/R was reduced by p38 mitogen-activated protein kinase inhibition (MKI). (D) Densitometry data of caspase-1 (% of procaspase-1). Active caspase-1 levels were increased after I/R. However, increased caspase-1 activation after I/R was reduced by p38 MAPK inhibition. (Mean ± standard error of the mean [n = 3 to 9/group]). *p < 0.05 versus control. p < 0.05 versus I/R alone.

View larger version (37K): [in this window] [in a new window]   Fig 6. Expression of active caspase-3 in ischemia-reperfusion (I/R) alone and I/R + p38 mitogen-activated protein kinase inhibitor (MKI) rat hearts. (A) Representative immunoblots of active caspase-3 (p20 and p17 subunits). (B) Densitometry data of active caspase-3 (p20 and p17) (% of caspase-3 p20, p17 in I/R alone group, respectively). (Mean ± standard error of the mean [n = 3/group].) *p < 0.05. **p < 0.001 versus I/R alone.

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

p38 MAPK is activated by ischemia and reperfusion [7, 10, 11, 13]. In the current study, p38 MAPK inhibition resulted in a marked decrease in myocardial injury and a significant increase in myocardial function during reperfusion (Fig 2). To assess the relative contribution of systolic versus diastolic improvement in the recovery of left ventricular developed pressure, we also analyzed left ventricular systolic pressure. Surprisingly, we found that there was no difference with p38 MAPK inhibition on left ventricular systolic pressure. This suggests that the improvement in left ventricular developed pressure produced by p38 MAPK inhibition was due to improvement in diastolic function (LVEDP). Thus it appears that p38 MAPK inhibition acts predominantly by decreasing the "stiffness" of the heart. However, we observed an approximately equal improvement in +dP/dt and –dP/dt. As dP/dt is dependent on loading conditions and the LVEDP between the two groups is different, we believe that this might have led to the differences in +dP/dt, although the contractility and systolic function might be similar.

The p38 MAPK inhibition resulted in a slight decrease of LVEDP during the 25-minute period of ischemia compared with I-R alone. However, a marked decrease of LVEDP was observed after 20 minutes of reperfusion with p38 MAPK inhibition. This observation is consistent with studies in which ischemia alone resulted in a moderate increase in p38 MAPK activation, whereas significantly greater activation of p38 MAPK was observed with the addition of reperfusion [10, 14]. It is evident that activation of p38 MAPK is an important signaling step in the development of myocardial injury, and this process may be related to its role in promoting proinflammatory cytokine production.

The I-R injury induces the local production of TNF, IL-1ß, and IL-6 [15–17]. It is now known that cardiomyocyte production of proinflammatory cytokines is partly responsible for myocardial dysfunction after acute injury [3, 18, 19]. Recently p38 MAPK activation has been correlated with proinflammatory cytokine production in myocardium after endotoxemia and burn trauma [8, 20]. However, whether activation of p38 MAPK plays an important role in postischemic myocardial inflammatory cytokine production is less clear. In this regard, p38 MAPK inhibition resulted in decreased postischemic myocardial TNF, IL-1ß, and IL-6 production, and their production occurred independent of blood-borne elements. The results presented here indicate that I-R injury-induced myocardial production of TNF, IL-1ß, and IL-6 is correlated with physiologic dysfunction and injury, and p38 MAPK inhibition attenuates both physiologic dysfunction-injury and myocardial inflammatory cytokine production.

In this study, we demonstrated that expression of TNF was decreased by p38 MAPK inhibitor administration after I-R. This finding is consistent with other studies showing that TNF production after I-R is dependent on p38 MAPK activation [4, 5], and regulation of this process may occur at the pre-transcriptional level (Fig 1). Similarly, the effects of p38 MAPK on IL-1ß and IL-6 may involve signaling steps proximal to the final active forms of these cytokines. Recently, caspase-1 and caspase-11 were shown to function upstream of IL-1ß maturation [21]. Interleukin-1ß is initially synthesized as an inactive precursor requiring the IL-1ß-converting enzyme or caspase-1 for cleavage to the mature, biologically active molecule [22, 23]. Interleukin-1ß-converting enzyme was required for IL-1ß activation in the postischemic heart [24]. Activation of caspase-1 is dependent on caspase-11 [25]. Caspase-11 is believed to activate downstream signals caspase-1 and caspase-3, and thus it may be important in both inflammation and apoptosis. It has been demonstrated that caspase-11 induced by lipopolysaccharide and hypoxia in microglia was mediated through p38 MAPK [26, 27]. Our results indicate that p38 MAPK inhibition reduces activation of caspase-11, which may result in decreased caspase-1 (IL-1ß-converting enzyme) and subsequent inhibition of IL-1ß production. This study is the first to correlate myocardial IL-1ß production with caspase-1 and caspase-11 activation through a p38 MAPK-mediated pathway.

The role of p38 MAPK in IL-6 production is less clear. There is evidence that p38 MAPK regulates IL-6 production in vascular smooth muscle cells by activating the cAMP response (CRE) site and cAMP response site binding protein (CREB) [28]. However, it is possible that the reduction in IL-6 is directly related to the SB 203580-induced decrease in TNF and IL-1ß, which stimulates IL-6 production [29, 30]. Indeed, in a previous study, we demonstrated that sequestering TNF with TNF binding protein reduced IL-6 to a level similar to that observed after SB 203580 administration in the heart exposed to lipopolysaccharide [20].

Evidence indicates that improved functional recovery and decreased myocardial injury with p38 MAPK inhibition correlates with decreased proinflammatory cytokine production and decreased activation of caspase-1, caspase-3, and caspase-11. Further understanding of the signaling pathways involved in injury-induced myocardial inflammation and methods of limiting these deleterious effects may translate into clinically applicable therapeutics and single site inhibition of both cytokine production and proapoptotic signaling.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This work was supported in part by the National Institutes of Health grant no. R01GM70628 (DRM).

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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