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Cardiovascular Research 2007 76(3):465-472; doi:10.1016/j.cardiores.2007.08.001
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Copyright © 2007, European Society of Cardiology

The relationship between p38 mitogen-activated protein kinase and AMP-activated protein kinase during myocardial ischemia

Sebastien Jacqueta, Elham Zarrinpashnehb, Audrey Chaveyc, Audrey Ginionb, Isabelle Leclercc, Benoit Violletd, Guy A. Rutterc, Luc Bertrandb and Michael S. Marbera,*

aCardiovascular Division, King's College London, St. Thomas' Hospital, London SEI 7EH, UK
bDivision of Cardiology, School of Medicine, Université Catholique de Louvain, Brussels, Belgium
cDepartment of Cell Biology, Division of Medicine, Imperial College, London SW7 2AZ, UK
dInstitut Cochin, Université Paris Descartes, CNRS (UMR 8104) and Inserm, U567, Paris, France

*Corresponding author. Department of Cardiology, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK. Tel.: +44 20 7188 1008; fax: +44 20 7188 0970. michael.marber{at}kcl.ac.uk

Received 31 May 2007; revised 19 July 2007; accepted 1 August 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective p38 mitogen-activated protein kinase (p38 MAPK) and AMP-activated protein kinase (AMPK) are activated by, and influence sensitivity to, myocardial ischemia. Recently a number of studies have suggested that AMPK may participate in the activation of p38 MAPK. We therefore examined whether AMPK may be the principal "ischemia sensor" responsible for p38 MAPK activation during myocardial ischemia.

Methods We used a variety of approaches to alter AMPK activity during ischemia and studied the repercussions on p38 MAPK activation.

Results The activities of AMPK and p38 MAPK were temporally related in adult rat ventricular myocytes (ARVM) subjected to simulated ischemia and in isolated mouse hearts subjected to no-flow ischemia. However p38 MAPK activation was unaltered in mouse hearts lacking the predominant or minor myocardial isoforms, AMPK{alpha}2 or AMPK{alpha}1 respectively. Likewise, in ARVM, adenoviral-driven expression of the minor myocardial isoform AMPK{alpha}1, in a constitutively active or dominant negative form reducing AMPK activity, did not alter p38 MAPK activation under basal conditions or during simulated ischemia. Finally, pharmacological inhibition of AMPK during ischemia with compound C did not attenuate the coincident activation of p38 MAPK.

Conclusions Although AMPK and p38 MAPK are both activated during myocardial ischemia, the activation of p38 MAPK occurs independently of AMPK.

KEYWORDS Ischemia; Heart; p38-MAPK; AMPK


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine kinase comprising a catalytic {alpha}, and two regulatory subunits [1]. In the heart, the dominant catalytic subunit is the {alpha}2 isoform [1]. AMPK activity is controlled allosterically by AMP and/or by phosphorylation of Thr172 in the activation loop of the catalytic {alpha} subunits by upstream kinases including the tumour suppressor LKB1 (also called STK11), Ca2+/calmodulin kinase kinase and TGF-beta-activated kinase-1 (TAK1) [2–4]. AMP concentration rises markedly during myocardial ischemia and is thought to account for AMPK activation under these circumstances [1].

Myocardial ischemia also activates a number of other kinases including the stress activated protein kinase p38, a member of a highly conserved subfamily of mitogen-activated protein kinases (MAPKs) [5]. Activation of p38 MAPK occurs through phosphorylation of both a threonine and a tyrosine residue within a conserved TGY motif in the activation loop. Classically this is achieved by proximal upstream MAP kinase kinases (MKK), such as MKK3, 6 and perhaps 4 [6]. More recently alternative, MKK-independent, mechanisms involving autophosphorylation of the TGY motif have been described [5–7]. One such mechanism, thought to occur during myocardial ischemia, involves a scaffold protein TAK1-binding protein (TAB1) [5,8,9] which is in turn phosphorylated by p38 and other kinase(s) on Ser423, Thr431 and Ser438 [10].

A number of independent groups have shown that the inhibition of p38 MAPK during prolonged ischemia leads to protection [5,8,11]. Unfortunately, it is also clear that p38 MAPK inhibition during the brief ischemia/reperfusion cycles of preconditioning prevents protection [12]. Thus blanket inhibition of p38 MAPK is unattractive as a therapeutic modality. Consequently, interest has increased in the mechanisms by which p38 MAPK becomes activated during prolonged ischemia since this may allow circumstance-specific inhibition. A number of reports have suggested that AMPK activation leads to p38 MAPK activation in various tissues including the heart [9,11,13]. The purpose of the current study was to directly examine this relationship during myocardial ischemia by manipulating AMPK expression and activity.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1 Materials
Antibodies recognizing the dual phospho-(Thr180/Tyr182) form of p38 MAPK (#9211), total p38 MAPK (#9212), phospho-Ser79 of the AMPK substrate Acetyl-CoA Carboxylase (ACC) (#3661), total AMPK{alpha} (#2532) and phospho-Thr172 of AMPK{alpha} (#2535) were from cell signaling (#product number). The anti AMPK{alpha}1 antibody is generated in house. The polyclonal antibodies to phospho-Ser423 and Ser438 of TAB1 were gifted by Professor P. Cohen's group (University of Dundee, U.K.) and used with the corresponding dephosphopeptide to enhance specificity [10]. All the antibodies were used at a dilution of 1/1000. SB203580 was obtained from Sigma-Aldrich and dissolved in DMSO (0.1% DMSO) as vehicle and controls received vehicle alone. Compound C was obtained from Calbiochem.

2.2 Isolated mouse heart perfusion
All animal experiments were carried out in accordance with Home Office regulations as detailed in the Home Office Guidance on the Operation of Animals (Scientific Procedures) Act 1986, HMSO (London) which mirrors those found in the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

Male C57BL/6 mice and male transgenic mice were anaesthetized and their hearts rapidly excised and perfused as previously described [4,14]. Briefly, hearts were retrogradely perfused at 37 °C with modified Krebs–Henseleit (K–H) buffer containing, in mM: NaCl 118.5, NaHCO3 25.0, KCl 4.75, KH2PO4 1.18, MgSO4 1.19, D-glucose 11.0, CaCl2 1.5 at a constant perfusion pressure of 75 mm Hg. For inclusion, all hearts had to fulfill the following criteria: coronary flow between 1.5 and 4.5 mL/min, heart rate >300 bpm (unpaced), left ventricular developed pressure >55 mm Hg, time from thoracotomy to aortic cannulation <3 min, and no persistent dysrhythmia during stabilization. After the stabilization period, hearts were subjected to 10 min of continued perfusion or no-flow ischemia before freeze clamping and storage at –80 °C. When specified, hearts were perfused with compound C (12 µM) for 10 min. All genetically modified mice were compared to their appropriate littermates [15].

2.3 Adult rat ventricular myocyte (ARVM) culture
ARVMs were isolated as previously described [16], and washed with M199 medium with added penicillin (100 I.U./ml) and streptomycin (100 I.U./ml). The cell suspension was centrifuged at 100 g for 2 min to pellet the myocytes, which were then resuspended in M199 complete medium (M199 medium with added penicillin 100 I.U./ml, streptomycin 100 I.U./ml, L-carnitine 2 mM, creatine 5 mM and taurine 5 mM) and placed in laminin-coated 6-well plates prior to incubation in 5% CO2/room air at 37 °C. After 1 h, the medium was aspirated, leaving only adherent cells, and fresh prewarmed M199 complete medium was added with specified adenoviral vectors.

2.4 Adenoviral infection of ARVM
Adenoviruses encoding c-myc-tagged forms of dominant negative AMPK{alpha}1 (AMPK-DN, Asp157 to Ala) and truncated constitutively active AMPK{alpha}1 (AMPK-CA, residues 1–312 with a Thr172 to Asp) as described previously [17] were added at a multiplicity of infection of 100 (providing approximately 95% transfection efficiency). Cells were exposed to virus for 16 h prior to washing and incubation in virus-free M199 complete medium for 24 h prior to simulated ischemia.

2.5 Simulated ischemia (SI) protocol
SI was induced by treating ARVMs for the specified time with a modifed K–H buffer (NaCl 137 mM, KCl 3.8 mM, MgCl2 0.49 mM, CaCl2 0.9 mM and Hepes 4.0 mM) with 2-deoxyglucose 10 mM, sodium lactate 20 mM, sodium dithionite 1 mM, at pH 6.5 [18]. For p38 MAPK inhibition studies, cells were exposed to SB203580 10 µM for 60 min prior to, and during, simulated ischemia. Following SI, the buffer was removed and ARVMs were quickly frozen, and stored, in liquid nitrogen.

2.6 Polyacrylamide gel electrophoresis and Western blot analysis
AVRMs and hearts were homogenized and solubulized in an SDS-PAGE sample buffer as previously described [5,14]. Proteins were separated on 10% SDS-polyacrylamide gels for all proteins of interest except for Acetyl-CoA carboxylase (ACC) (5% gel) and transferred to PVDF membranes which were blocked for 2 h with 5% nonfat milk +1%BSA in TRIS-buffered saline (pH 7.4) containing 0.1% Triton (TBST) and probed overnight at 4 °C with the appropriate primary antibody. After washing and exposure for 2 h at room temperature to HRP-conjugated secondary antibody (Amersham-Biosciences), antibody–antigen complexes were visualized by enhanced chemiluminescence. The quantification of band intensity was performed using a Quantity One (version 4.5) software following digitization using a GS-800 scanner, both from Bio-Rad. Densitometric values in arbitrary density units of the phosphorylated proteins are normalized to the total amount of the protein detected.

2.7 Statistical analysis
Results are expressed as mean±SD. All data sets were analysed by one-way analysis of variance followed by Tukey Multiple Comparison. A value of P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1 Activation of AMPK is accompanied by p38 MAPK activation during ischemia
Adult rat ventricular myocytes (ARVM) were subjected to simulated ischemia of varied duration (Fig. 1A). Robust activating phosphorylation of p38 MAPK and AMPK were observed beyond 20 min (Fig. 1B) and this was associated with the phosphorylation of the respective downstream substrates, Ser423 of TAB1 and Ser79 of ACC. In the whole heart we examined AMPK and p38 MAPK activation after 10 min of no-flow ischemia (Fig. 1C), a time point of reproducible activation in this model. [5] Reflecting findings with simulated ischemia, AMPK and p38 MAPK activating phosphorylations were coincident, and were mirrored by phosphorylation of respective downstream substrates.


Figure 1
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  		Fig. 1 Effect of ischemia on AMPK and p38 MAPK activation. A; Time course of AMPK and p38 MAPK phosphorylation during simulated ischemia (SI) in adult rat ventricular myocytes (ARVMs). AVRMs were exposed to SI and harvested for analysis of AMPK and p38 MAPK activating phosphorylations at the indicated time points (min). Samples were analysed by immunoblotting with antibodies recognizing dual phosphorylated p38 MAPK, phospho-Thr172 of AMPK, phospho-Ser79 of ACC, phospho-Ser423 of TAB1, phospho-Ser438 of TAB1 and total p38 MAPK. The immunoblot is representative of three independent experiments. B; Quantification of phosphorylated p38 MAPK and phosphorylated AMPK from the Western blot of Fig. 1A. C; Effect of no-flow ischemia on AMPK and p38 MAPK activity in perfused mouse heart. Mouse hearts were retrogradely and aerobically perfused for 25 min (control) or 15 min followed by 10 min of normothermic no-flow ischemia (ischemia), prior to harvesting. Protein samples were fractionated by SDS-PAGE and immunoblotted using the same antibodies as in Fig. 1A. The immunoblot is representative of five different hearts per group.

 
3.2 p38 MAPK activation occurs during ischemia in hearts lacking AMPK{alpha}2 catalytic activity
To further examine the relationship between AMPK and p38 MAPK activation during ischemia we used hearts from a previously characterised mouse line lacking exon3 (residues 189–260 of catalytic domain) in both AMPK{alpha}2 alleles (AMPK{alpha}2–/–) (Fig. 2) [19]. Hearts from these mice are phenotypically normal but total myocardial AMPK activity is markedly reduced due to a lack of compensatory upregulation of the less abundant AMPK{alpha}1 catalytic subunit [4]. Consequently, AMPK{alpha}1/2 immunoreactivity was strikingly diminished in AMPK{alpha}2–/–hearts. During ischemia some activating phospho-Thr immunoreactivity is seen in AMPK{alpha}2–/–hearts but the remaining AMPK{alpha}1 activity is insufficient to cause robust activation of the direct downstream substrate ACC. Despite this marked reduction in AMPK{alpha} catalytic protein abundance and activity during ischemia, p38 MAPK dual phosphorylation/activation is unaffected.


Figure 2
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  		Fig. 2 Effect of AMPK{alpha}2 gene deletion on p38 MAPK phosphorylation during no-flow myocardial ischemia. Wild type and AMPK{alpha}2–/–mouse hearts were retrogradely perfused and prepared as described in legend to Fig. 1C. A total AMPK antibody was used to confirm the genotype of the mice. The immunoblot is representative of five different hearts per group quantified in the bar graph ***p<0.005, ns=not significant.

 
3.3 AMPK{alpha}1 does not influence p38 MAPK activation in ARVMs subjected to simulated ischemia or in isolated mouse hearts subjected to true ischemia
Fig. 2 demonstrates that the AMPK{alpha}2–/–hearts displayed some residual AMPK{alpha}1 activity and that this perhaps may have contributed to the continued dual phosphorylation of p38 MAPK during ischemia. We therefore examined this possibility by expressing constitutively active (CA) or kinase-dead (DN) forms of AMPK{alpha}1 in ARVMs. Fig. 3A demonstrates that under basal conditions the truncated active form of AMPK{alpha}1 increased ACC phosphorylation whilst, during simulated ischemia (Fig. 3B), the kinase-dead form diminished ACC phosphorylation. The latter observation suggests that the dominant negative AMPK{alpha}1 was also able to inhibit the {alpha}2 catalytic subunit by binding the common {alpha}1 and {alpha}2 scaffold subunits, as described previously [20,21]. Nonetheless, neither the CA-form under basal conditions, nor the DN-form during simulated ischemia, altered p38 MAPK dual phosphorylation. Simulated ischemia resulted in robust p38 MAPK dual phosphorylation (see Fig. 1A and compare Fig. 3A with B), which was inhibited by SB203580 as was the downstream phosphorylation of Ser423 of TAB1. The slight decrease in pACC during simulated ischemia in the presence of SB203580 maybe explained by the fact that p38 MAPK could be upstream of AMPK [22].


Figure 3
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  		Fig. 3 Effect of expression of DN/CA AMPK{alpha}1 in ARVMs subjected to simulated ischemia or of AMPK{alpha}1 gene deletion during true ischemia on p38 MAPK phosphorylation. ARVMs were exposed to adenoviral vectors encoding AMPK-DN, AMPK-CA or GFP at a MOI of 100. As indicated, cells were exposed to 10 µM SB203580 (SB) for 1 h, and/or simulated ischemia (panel B) for 40 min, prior to harvesting. Proteins were separated and visualised as described in legend Fig. 1. Immunoreactive AMPK appears as two bands the upper one corresponding to the AMPK-DN form and the lower one to the truncated AMPK-CA form. Bar graph represents the quantification of the p38 MAPK dual phosphorylation signal in the absence of SB, n=4, ***p<0.005. Panel C is a verification of the lack of a role for AMPK{alpha}1 in p38 MAPK activation during true, rather than simulated ischemia using AMPK{alpha}1 null mouse hearts (n=3) and protocols as described in Fig. 1C.

 
To further verify that AMPK{alpha}1 does not influence p38 MAPK activation during true ischemia we analysed hearts from AMPK{alpha}1–/–mice [23] as described in Fig. 2. Fig. 3C demonstrates that p38 MAPK activation during ischemia is unaltered in the absence of AMPK{alpha}1. The higher level of basal phospho-P38 in those mice compared to the AMPK{alpha}2–/–mice may be due to a slightly different strain background (C57Bl6/129Sv/FVB-N) [15].

3.4 Pharmacological inhibition of AMPK activity does not prevent p38 MAPK activation in hearts to be subjected to global ischemia
Fig. 4 demonstrates that compound C diminished the phosphorylation of ACC during ischemia indicating effective pharmacological inhibition of AMPK: note that phosphorylation of AMPK at Thr-172 was unaffected in these experiments consistent with an action to block AMPK catalytic activity rather upstream kinases. Despite this, the activating dual phosphorylation of p38 MAPK was unchanged.


Figure 4
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  		Fig. 4 Effect of inhibition of AMPK activity by compound C on p38 MAPK phosphorylation in hearts subjected to global ischemia. Wild type mouse hearts (n=5) were retrogradely perfused and prepared as described in legend to Fig. 1C. Where indicated, mouse hearts were perfused with compound C (12 µM) for 10 min before ischemia.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
The activation of p38 MAPK during myocardial ischemia has a number of consequences that make an understanding of the underlying mechanism of paramount importance. Despite the attraction of AMPK as a candidate coordinating kinase, we were unable in the present study to moderate the ischemic activation of p38 MAPK despite markedly inhibiting AMPK activity through a variety of diverse routes.

Numerous independent investigators have found that p38 MAPK becomes active during myocardial ischemia and contributes to injury [5,8,11]. Since this kinase is essential for development, [24] and under other circumstances initiates protection [12], we suggest that the exact upstream or downstream events associated with this activation may yield a more useful therapeutic target(s) than p38 MAPK itself. Surprisingly, pyridyl-imidazole-based catalytic inhibitors of p38 MAPK diminish its activating dual phosphorylation during myocardial ischemia [5,8,11], but not necessarily with other stresses. These inhibitors should just prevent downstream phosphorylation since they do not inhibit the upstream MKKs responsible for dual phosphorylation. Thus the observed reduction in p38 MAPK dual phosphorylation with pyridyl-imidazole inhibitors may provide a clue to the mechanism of activation. There are two potential explanations underlying this observation. The first possibility is that the pyridyl-imidazoles are inhibiting other kinases [25] activated during ischemia upstream of the MKKs as a result of their known nonselective actions [26]. The second possibility is that p38 MAPK catalytic activity is required to cause its own dual phosphorlyation. Although controversial, a number of lines of evidence suggest that this later explanation is more likely during myocardial ischemia and occurs through an association with the scaffold protein TAB1 [5,8,9,11].

The question remains as to how the association between TAB1 and p38 MAPK is promoted during ischemia? Ischemia comprises a number of components such as acidosis and osmotic stress that can independently activate p38 MAPK [5,27]. However, in the heart osmotic stress causes p38 MAPK activation that is neither sensitive to pyridyl-imidazoles nor dependent on a p38 MAPK-TAB1 association [5] whilst acidosis-induced activation is MKK-dependent [27]. Another possibility is that the ischemia is sensed by perturbations in metabolism. AMPK is strongly activated during ischemia of the heart and other organs. [1] Furthermore a number of studies have suggested p38 MAPK lies downstream of AMPK based on pharmacological [28,29], or genetic [28,30], manipulation. Hence we used a variety of reagents to examine if such a relationship can explain the activation of p38 MAPK during myocardial ischemia. Although the activation of p38 MAPK accompanied that of AMPK, the former was not altered by a variety of diverse interventions that profoundly affected AMPK activation and the phosphorylation state of a bona fide downstream target like ACC. Therefore, our results strongly suggest that AMPK is not, or at least not chiefly, responsible for p38 MAPK activation under this circumstance.

Recently, AMPK{alpha}2, but not AMPK{alpha}1, was found to co-associate with TAB1 in ischemic myocardium [9]. A causal role was implied by the finding that this association, as well as that with p38 MAPK, was absent in hearts from mice transgenic for a dominant negative form of AMPK{alpha}2 (K54R) expressed in cardiac myocytes [9]. Moreover the activation of p38 MAPK was deficient in the transgenic hearts [9]. Understandably, the authors concluded that AMPK activates p38 MAPK by enhancing its recruitment to TAB1. These findings differ from our own where the absence of AMPK{alpha}2 protein, or the presence of the protein, but the absence of its activation during ischemia, has no influence on p38 MAPK activation. We believe the most likely explanation for this dichotomy is due to transgene specific effects. For example the AMPK{alpha}2 (K54R) dominant negative [9,31], differs from the AMPK{alpha}2 (D157A) dominant negative [32] and from the AMPK{alpha}2 null mouse [19] in that heart size and contractility are reduced at baseline. Furthermore given the numerous independent, molecular approaches we have taken here to perturb the ischemic activation of AMPK it seems unlikely that their lack of effect on p38 MAPK activity are the result of agent-specific idiosyncrasies.

In keeping with our findings Jaswal et al. [22] have recently shown that AMPK does not lie upstream of p38 MAPK, but rather downstream. This finding may relate to an indirect relationship between p38 MAPK and AMPK through the modulation of a common upstream kinase TAK1 [3,10].

In summary, our findings, and those of others, do not support the premise that p38 MAPK lies downstream of AMPK.

Time for primary review 26 days


   Acknowledgements
 
The anti-phospho TAB1 antibodies were provided by Sir Philip Cohen, MRC Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom.

Sources of funding: This study was supported by a grant from the Wellcome Trust (074653), British Heart Foundation and by a grant from the Fonds National de la Recherche Scientifique et Médicale, Belgium. We thank Semjidmaa Dashnyam, who was funded through the Medical Research Council Co-operative Group Core Grant (G0001112), for her help in myocyte isolation. GAR was supported by the Wellcome Trust Programme Grants (067081/Z/02/Z, 081958/Z/07/Z) and Research Leave Fellowship, and NIH (RO1 DK071962-01) and MRC (G0401641). Research grants The Fonds Spéciaux de Recherche, UCL, BELGIUM, funded EZ. LB is a Research associate of the Fonds National de la Recherche Scientifique, Belgium.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

  1. Dolinsky V.W., Dyck J.R. Role of AMP-activated protein kinase in healthy and diseased hearts. Am J Physiol Heart Circ Physiol (2006) 291:H2557–H2569.[Abstract/Free Full Text]
  2. Wang M., Tsai B.M., Turrentine M.W., Mahomed Y., Brown J.W., Meldrum D.R. p38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart. Ann Thorac Surg (2005) 80:2235–2241.[Abstract/Free Full Text]
  3. Xie M., Zhang D., Dyck J.R., Li Y., Zhang H., Morishima M., et al. A pivotal role for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc Natl Acad Sci U S A (2006) 103:17378–17383.[Abstract/Free Full Text]
  4. Zarrinpashneh E., Carjaval K., Beauloye C., Ginion A., Mateo P., Pouleur A.C., et al. Role of the alpha2-isoform of AMP-activated protein kinase in the metabolic response of the heart to no-flow ischemia. Am J Physiol Heart Circ Physiol (2006) 291:H2875–H2883.[Abstract/Free Full Text]
  5. Tanno M., Bassi R., Gorog D.A., Saurin A.T., Jiang J., Heads R.J., et al. Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation: evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia. Circ Res (2003) 93:254–261.[Abstract/Free Full Text]
  6. Kang Y.J., Seit-Nebi A., Davis R.J., Han J. Multiple activation mechanisms of p38alpha mitogen-activated protein kinase. J Biol Chem (2006) 281:26225–26234.[Abstract/Free Full Text]
  7. Ge B., Gram H., Di Padova F., Huang B., New L., Ulevitch R.J., et al. MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science (2002) 295:1291–1294.[Abstract/Free Full Text]
  8. Fiedler B., Feil R., Hofmann F., Willenbockel C., Drexler H., Smolenski A., et al. cGMP-dependent protein kinase type I inhibits TAB1-p38 mitogen-activated protein kinase apoptosis signaling in cardiac myocytes. J Biol Chem (2006) 281:32831–32840.[Abstract/Free Full Text]
  9. Li J., Miller E.J., Ninomiya-Tsuji J., Russell R.R. III, Young L.H. AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing its recruitment to TAB1 in the ischemic heart. Circ Res (2005) 97:872–879.[Abstract/Free Full Text]
  10. Cheung P.C., Campbell D.G., Nebreda A.R., Cohen P. Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. EMBO J (2003) 22:5793–5805.[CrossRef][Web of Science][Medline]
  11. Capano M., Crompton M. Bax translocates to mitochondria of heart cells during simulated ischaemia: involvement of AMP-activated and p38 mitogen-activated protein kinases. Biochem J (2006) 395:57–64.[CrossRef][Web of Science][Medline]
  12. Sanada S., Kitakaze M., Papst P.J., Hatanaka K., Asanuma H., Aki T., et al. Role of phasic dynamism of p38 mitogen-activated protein kinase activation in ischemic preconditioning of the canine heart. Circ Res (2001) 88:175–180.[Abstract/Free Full Text]
  13. Du J.H., Xu N., Song Y., Xu M., Lu Z.Z., Han C., et al. AICAR stimulates IL-6 production via p38 MAPK in cardiac fibroblasts in adult mice: a possible role for AMPK. Biochem Biophys Res Commun (2005) 337:1139–1144.[Web of Science][Medline]
  14. Bellahcene M., Jacquet S., Cao X.B., Tanno M., Haworth R.S., Layland J., et al. Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor. J Am Coll Cardiol (2006) 48:545–555.[Abstract/Free Full Text]
  15. Goirand F., Solar M., Athea Y., Viollet B., Mateo P., Fortin D., et al. Activation of AMP kinase {alpha}1 subunit induces aortic vasorelaxation in mice. J Physiol (2007) 581:1163–1171.[Abstract/Free Full Text]
  16. Saurin A.T., Martin J.L., Heads R.J., Foley C., Mockridge J.W., Wright M.J., et al. The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. FASEB J (2000) 14:2237–2246.[Abstract/Free Full Text]
  17. da Silva Xavier G., Leclerc I., Varadi A., Tsuboi T., Moule S.K., Rutter G.A. Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J (2003) 371:761–774.[CrossRef][Web of Science][Medline]
  18. Punn A., Mockridge J.W., Farooqui S., Marber M.S., Heads R.J. Sustained activation of p42/p44 mitogen-activated protein kinase during recovery from simulated ischaemia mediates adaptive cytoprotection in cardiomyocytes. Biochem J (2000) 350(Pt 3):891–899.[CrossRef][Web of Science][Medline]
  19. Viollet B., Andreelli F., Jorgensen S.B., Perrin C., Geloen A., Flamez D., et al. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J Clin Invest (2003) 111:91–98.[CrossRef][Web of Science][Medline]
  20. Rutter G.A., Da Silva Xavier G., Leclerc I. Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J (2003) 375:1–16.[CrossRef][Web of Science][Medline]
  21. Witters L.A., Kemp B.E., Means A.R. Chutes and ladders: the search for protein kinases that act on AMPK. Trends Biochem Sci (2006) 31:13–16.[CrossRef][Web of Science][Medline]
  22. Jaswal J.S., Gandhi M., Finegan B.A., Dyck J.R., Clanachan A.S. p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5'-AMP-activated protein kinase. Am J Physiol Heart Circ Physiol (2007) 292:H1978–H1985.[Abstract/Free Full Text]
  23. Jorgensen S.B., Viollet B., Andreelli F., Frosig C., Birk J.B., Schjerling P., et al. Knockout of the alpha2 but not alpha1 5'-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranosidebut not contraction-induced glucose uptake in skeletal muscle. J Biol Chem (2004) 279:1070–1079.[Abstract/Free Full Text]
  24. Tamura K., Sudo T., Senftleben U., Dadak A.M., Johnson R., Karin M. Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell (2000) 102:221–231.[CrossRef][Web of Science][Medline]
  25. Godl K., Wissing J., Kurtenbach A., Habenberger P., Blencke S., Gutbrod H., et al. An efficient proteomics method to identify the cellular targets of protein kinase inhibitors. Proc Natl Acad Sci U S A (2003) 100:15434–15439.[Abstract/Free Full Text]
  26. Ping P., Murphy E. Role of p38 mitogen-activated protein kinases in preconditioning: a detrimental factor or a protective kinase? Circ Res (2000) 86:921–922.[Free Full Text]
  27. Zheng M., Reynolds C., Jo S.H., Wersto R., Han Q., Xiao R.P. Intracellular acidosis-activated p38 MAPK signaling and its essential role in cardiomyocyte hypoxic injury. FASEB J (2005) 19:109–111.[Abstract/Free Full Text]
  28. Pelletier A., Joly E., Prentki M., Coderre L. Adenosine 5'-monophosphate-activated protein kinase and p38 mitogen-activated protein kinase participate in the stimulation of glucose uptake by dinitrophenol in adult cardiomyocytes. Endocrinology (2005) 146:2285–2294.[Abstract/Free Full Text]
  29. Young L.H., Li J., Baron S.J., Russell R.R. AMP-activated protein kinase: a key stress signaling pathway in the heart. Trends Cardiovasc Med (2005) 15:110–118.[CrossRef][Web of Science][Medline]
  30. Xi X., Han J., Zhang J.Z. Stimulation of glucose transport by AMP-activated protein kinase via activation of p38 mitogen-activated protein kinase. J Biol Chem (2001) 276:41029–41034.[Abstract/Free Full Text]
  31. Russell R.R. III, Li J., Coven D.L., Pypaert M., Zechner C., Palmeri M., et al. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest (2004) 114:495–503.[CrossRef][Web of Science][Medline]
  32. Xing Y., Musi N., Fujii N., Zou L., Luptak I., Hirshman M.F., et al. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. J Biol Chem (2003) 278:28372–28377.[Abstract/Free Full Text]

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