Skip Navigation

Cardiovascular Research 2004 61(1):123-131; doi:10.1016/j.cardiores.2003.09.034
© 2004 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gorog, D. A
Right arrow Articles by Marber, M. S
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gorog, D. A
Right arrow Articles by Marber, M. S
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2004, European Society of Cardiology

Inhibition of p38 MAPK activity fails to attenuate contractile dysfunction in a mouse model of low-flow ischemia

Diana A Goroga, Masaya Tannoa, Xuebin Caoa, Mohamed Bellahcenea, Rekha Bassia, Alamgir M.N Kabira, Kushal Dighea, Roy A Quinlanb and Michael S Marber*,a

aDivision of Cardiology, KCL, The Rayne Institute, St. Thomas' Hospital, London, UK
bSchool of Biological and Biomedical Sciences, University of Durham, Durham, UK

* Corresponding author. Tel.: +44-207-922-8191; fax: +44-207-960-9659. mike.marber{at}kcl.ac.uk

Received 19 August 2003; revised 11 September 2003; accepted 30 September 2003


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: The basal activity of p38 MAPK has recently been shown to impair myocardial contractility. This kinase is activated by ischemia and short-term hibernation. We hypothesized that p38 MAPK activation may contribute to the contractile deficit that characterizes low-flow ischemia. Methods: In Langendorff-perfused isolated C57BL/6 mouse hearts, perfusion pressure was reduced from 85 to 15 or 30 mm Hg for 120 min to induce ischemic left ventricular dysfunction. The effect of the p38 MAPK inhibitor SB203580 (1 µM/l) on contractile function and p38 MAPK activation was assessed. Results: Reduction in perfusion pressure to 15 or 30 mm Hg was accompanied by stable reductions in coronary flow (83±2% and 66±2%, respectively) and developed pressure (84±2% and 61±3%), with minimal infarction (15.6±0.69% and 10.6±0.98% of LV myocardium, respectively), but marked activation of p38 MAPK (reflected in pHSP27 1092±326% basal and 996±301% basal, respectively). The p38 MAPK inhibitor SB203580, present during the last 60 min of reduced pressure perfusion, prevented p38 MAPK activation (pHSP27 281±92% basal, p = 0.01 and 186±72% basal, p = 0.01) but, despite the presence of a contractile reserve, had no effect on developed pressure. Similarly, early treatment with SB203580 started 5 min after the onset of reduced flow also failed to attenuate contractile dysfunction. Conclusion: The p38 MAPK activation that accompanies short-term hibernation does not appear to contribute to the contractile deficit.

KEYWORDS Contractile function; Ischemia; MAP kinase; Ventricular function; Hibernation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Hibernating myocardium makes a significant contribution to the burden of ischemic ventricular dysfunction, and its importance lies in the recognition that it responds to revascularization [1]. However, unfavourable coronary anatomy, coupled with the high surgical risk associated with poor ventricular function mean that relatively few such patients derive benefit from revascularization and there is currently no medical treatment available for improving the contractile dysfunction. The stress-induced p38 subfamily of mitogen activated protein kinases (MAPKs) are activated in response to various extracellular stimuli through dual phosphorylation of threonine and tyrosine residues at positions 180/182 [2] causing downstream phosphorylation of several other proteins, including heat shock protein 27 (HSP27) [3]. Activation of p38 MAPK has been documented in animals in response to ischemia/reperfusion [4], preconditioning [5], and pressure overload-induced cardiac hypertrophy [6] and in humans with heart failure [7,8]. Recent publications have demonstrated p38 MAPK activation in models of low-flow ischemia [9,10]. In cardiac myocytes, activation of p38 MAPK by beta adrenergic stimulation [11] or by gene transfer of an activated mutant of its upstream kinase MKK3bE [12], resulted in marked impairment in contractility, whilst inhibition with SB203580 or genetic manipulation improved basal contractility [12]. Furthermore, transgenic mice expressing MKK3bE exhibited histological features and expressed fetal marker genes similar to those seen in heart failure and had markedly impaired cardiac systolic function with premature death [13]. In contrast, in a recent extensive study where reductions in coronary flow purposefully caused appreciable infarction and abolition of regional systolic thickening, p38 MAPK inhibition had no effect on contractility [14]. However, it remains unknown whether p38 MAPK inhibition would improve contractility under less severe conditions designed to induce ischemic left ventricular dysfunction with minimal infarction, definite continued contraction and a demonstrable contractile reserve.

We hypothesized that p38 MAPK activation is involved in the mechanism of reduced contractility induced by low-flow ischemia/short-term hibernation and that inhibition of p38 MAPK activation could improve contractility.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
The investigation conforms with 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).

2.1 Heart isolation and perfusion
Male C57BL/6 mice were anaesthetised and their hearts rapidly excised and perfused as described previously [15]. The aorta was cannulated with a 23-guage blunt and grooved stainless steel needle and tied to the cannula with silk suture. The heart was retrogradely perfused with modified Krebs–Henseleit (K-H) buffer containing, in mmol/l: NaCl 118.5, NaHCO3 25.0, KCl 4.75, KH2PO4 1.18, MgSO4 1.19, D-glucose 11.0, CaCl2 1.41 at a constant perfusion pressure of 85 mm Hg. The buffer was prefiltered using a 0.8 µM micro-filter (Whatman, UK) and constantly bubbled through with 95% O2/5%CO2 gas. The left atrium was removed with scissors and a deflated balloon was inserted into the left ventricle through the mitral valve to monitor contractile function of the left ventricle. The balloon was attached to a pressure transducer, which was coupled to a 4S PowerLab (AD instruments, UK). The frequency responses of the isovolumic fluid filled balloon, coupling tubing and transducer were flat to at least 30 Hz. The balloon was gradually inflated until end-diastolic pressure reached between 2 and 5 mm Hg. The LV systolic, diastolic and developed pressures were displayed using Chart 4v.0.4 software (PowerLab, AD Instruments). The term ‘developed pressure’ was applied to the difference between systolic and diastolic pressures. The temperature of the heart was monitored continuously through a K-type thermocouple, inserted directly into the right ventricle and attached to a C9001 Thermometer (Comark, UK). The temperature was maintained at 37.0±0.1 °C by immersing the heart and cannula in modified K-H buffer kept at 37.0 °C in a water-jacketed chamber and maintaining the perfusion buffer in a similar thermostatically controlled water-jacketed system. Coronary flow was measured as the volume displaced over 1 min from the beaker containing modified K-H solution in which the perfused heart was immersed.

2.2 Experimental protocol
Following 30 min stabilization, perfusion pressure was reduced to 30, 25 and 20 mm Hg for 5 min each and then kept constant at 15 mm Hg for 120 min (low-flow group). In a second series, perfusion pressure was reduced to 30 mm Hg and kept constant for 120 min (moderate-flow group) (Fig. 1). After 60 min of reduced flow perfusion, the perfusate was switched to either modified Krebs–Henseleit (K-H) buffer containing 1 µM SB203580 (Sigma, UK) in 0.01% DMSO (Sigma) (SB+; low-flow: n = 10, moderate-flow: n = 8) or to 0.01% DMSO alone (SB–; low-flow: n = 8, moderate-flow: n = 8). To investigate the possibility that p38 MAPK-mediated impairment in contractility was involved only in the early stages of reduced flow, SB203580 or vehicle was administered after 5 min of low-flow (low-flow; early SB+n = 6, early SB–n = 6) and moderate-flow (moderate-flow; early SB+n = 6, early SB–n = 6). To assess the functional deterioration in the isolated heart preparation over time, a control series of experiments were performed where hearts (n = 9) were perfused for 150 min at a constant perfusion pressure of 85 mm Hg. At the end of the protocol, 5 hearts/group were stained with 1% triphenyl tetrazolium chloride (Sigma) and stored at –70 °C for analysis of infarct size (IS).


Figure 1
View larger version (32K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Perfusion protocols. K-H=modified Krebs–Henseleit solution. Vehicle=K-H solution containing 0.01% DMSO. PP=perfusion pressure. Arrowheads indicate the timepoint in the protocol when the contractile reserve in response to increased [Ca] perfusion was assessed (see Fig. 3).

 
To assess the reversibility of the contractile dysfunction, at the end of the protocol, the perfusion pressure was increased to 85 mm Hg for 30 min in three hearts in each series. To confirm the existence of a contractile reserve following 60 min reduced flow perfusion, the effect of increased calcium perfusion (K-H buffer containing 2.2 mM [Ca] (twofold increase); n = 5 per group) on contractility was assessed in hearts perfused with K-H buffer with and without SB203580 after the first 5 min of reduced flow.

2.3 Infarct size assessment
IS was assessed as previously described [15]. Hearts were thawed and placed in 2.5% gluteraldehyde for 1 min and set in 5% agarose. The agarose blocks were sectioned from apex to base in 0.7 mm slices using a vibratome (Agar Scientific, UK). Slices were placed overnight in 10% formaldehyde at room temperature, before transferring to phosphate buffered saline for a further day at 4 °C. Sections were then compressed between Perspex plates (0.57 mm apart) and imaged using a TK-1280E digital camera (JVC). After magnification x 25, planimetry was performed using image analysis software (NIH Image v1.61) and surface area transformed to volume by multiplication with tissue depth. IS was expressed as the percentage of area at risk (AAR), defined as the sum of total ventricular area minus cavities.

2.4 Western blotting
Tissue preparation and Western blot analysis were performed as previously described [15] using the following primary antibodies: mouse monoclonal antibody to phospho-specific p38 MAPK (Thr 180/Tyr 182) (Sigma Biosciences, UK); rabbit polyclonal and monoclonal antibodies for total p38 MAPK and phosphorylated HSP27 (Ser82), respectively; and goat antibody for total HSP27 (all Santa Cruz Biotechnology, CA, USA). Phosphorylated p38 was detected using a peroxidase-conjugated rabbit secondary antibody; total p38, total and phosphorylated HSP27 were detected with peroxidase-conjugated anti-goat antibody (all Dako, Denmark).

Densitometric analysis of the blots was performed to quantify the degree of phosphorylation using NIH image analysis software.

2.5 Statistical analysis
Data are presented as mean±S.E.M., except Table 1 (mean±S.D.). Hemodynamic parameters were compared using two-way repeat measures ANOVA with pairwise multiple comparison. The hemodynamic response to increased calcium and reperfusion was assessed using paired t-tests. Morphometric and baseline hemodynamic characteristics, infarct sizes and blot densities with and without SB203580 were compared using one-way ANOVA. p<0.05 was considered significant.


View this table:
[in this window]
[in a new window]

  		Table 1 Morphometric and hemodynamic characteristics after 30 min stabilization (mean±S.D.)

 

   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1 LV function
The SB+ and SB– groups were similar with regard to baseline characteristics and hemodynamic parameters at the end of stabilization (Table 1) and at 0, 30, 60, 90 and 120 min of low- or moderate-flow. Overall, reductions in perfusion pressure of 82% (low-flow) and 65% (moderate-flow) were associated with 83±2% and 66±2% reduction in coronary flow and 84±2% and 61±3% reduction in left ventricular developed pressure (LVDP), respectively, implying perfusion–contraction matching under both low- and moderate-flow conditions (Fig. 2, panels A and E). Switching the perfusate after 60 min to buffer containing SB203580 did not alter hemodynamics at either moderate or low-flow (Fig. 2, panels B and F). Early treatment with SB203580 after 5 min of reduced flow perfusion also failed to improve contractile function either under low- or moderate-flow conditions (Fig. 2, panels D and H).


Figure 2
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Hemodynamic parameters of hearts subjected to low-flow (Panels A–D) and moderate-flow (Panels E–H) perfusion. Arrows correspond to the change in perfusate from modified Krebs–Henseleit buffer to vehicle (upper panels) or SB203580 (lower panels). Values shown are mean±S.E.M. P>0.05 for comparison of hemodynamic parameters at 60 min with 90 and 120 min reduced flow for series A, B, E and F; and at 0 min with 15, 30, 60 and 90 min reduced flow for series C, D, G and H.

 
In reperfused hearts, LVDP recovered to 35±4% baseline, from 16±2% at the end of low-flow perfusion (p = 0.003) and to 62±3% baseline, from 44±2% at the end of moderate-flow perfusion (p = 0.003). Perfusion with K-H buffer containing 2.2 mM [Ca] increased LVDP by 52±30% from 10±3.5 mm Hg at the end of low-flow perfusion (p = 0.005) and by 41±15% from 24±1.4 mm Hg at the end of moderate-flow perfusion (p = 0.003), confirming the presence of a contractile reserve (Fig. 3). Contractile reserve was also preserved in hearts perfused with SB203580 after the first 5 min of reduced flow. In control hearts, the functional deterioration was minimal even after 150 min. At the end of the protocol, the mean deterioration in LVDP was only 15.9% of baseline, from 67±13 to 56±11 mm Hg, and similarly, coronary flow fell by only 17% from 3±1.1 to 2.6±0.7 ml/min. This deterioration did reach statistical significance on paired analysis, however, with unpaired analysis, the LVDP and coronary flow measurements at 150 min are still within the range of our baseline values.


Figure 3
View larger version (25K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Assessment of contractile reserve. Effect of perfusion with modified Krebs–Henseleit buffer containing 2.2 mM calcium on left ventricular developed pressure (LVDP) after 60 min low (LF) or moderate flow (MF), with and without SB203580 after the first 5 min reduced flow.

 
3.2 Infarct size
Infarct sizes were similar in SB+ and SB– hearts subjected to low-flow (IS/AAR 15.5±0.64% vs. 15.6±0.69%, p = 0.95) and moderate-flow (13.3±1.35% vs. 10.6±0.98%, p = 0.16). In the early SB+ group, infarct size was reduced compared to SB– group at both low-flow (7.1±0.79% vs. 15.6±0.69%, p<0.001) and moderate-flow (2.3±0.4% vs. 10.6±0.98%, p<0.001). The area at risk was not different between SB+ and SB– groups (data not shown). The IS after the control protocol of perfusion at 85 mm Hg for 150 min was 6.1±1.2%.

3.3 Western blot analysis
The total p38 MAPK and HSP27 protein content was similar between groups. Representative blots are shown in Fig. 4. Densitometry revealed p38 MAPK activation by low- or moderate-flow perfusion (288±43% basal, p = 0.01 and 336±13% basal, p = 0.01), which was reflected in HSP27 phosphorylation. This was inhibited by SB203580 (153±36% basal, p = 0.01 and 190±41% basal, p = 0.02).


Figure 4
View larger version (37K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Panel A. Western blots of total and phosphorylated p38 MAPK and HSP27 in hearts subjected to 120 min reduced flow perfusion, and perfused with vehicle (SB–) or SB203580 (SB+) following 60 min reduced flow. Low-flow (LF) and moderate-flow (MF) perfusion induced p38 MAPK phosphorylation, which was inhibited by SB203580. Activation of p38 MAPK is reflected in the phosphorylation of HSP27. Panel B. Western blots of hearts subjected to 30 min stabilization at 85 mm Hg followed by reduced flow for 60 min and perfused with vehicle (SB–) or SB203580 (SB+) after 5 min reduced flow. Control hearts subjected to 90 min perfusion at 85 mm Hg (baseline) are shown for comparison. Reduced flow perfusion induced p38 MAPK and HSP27 phosphorylation, which was inhibited by SB203580. Panel C. Quantitative data (mean±S.D., n = 3 per group) confirming abolition of p38 MAPK and HSP27 phosphorylation by SB203580 at 120 min.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
In an isolated mouse heart model, we have shown that p38 MAPK activation occurs during adaptation to low-flow and that administration of SB203580, a potent MAPK-inhibitor, after the establishment of steady state reduced flow perfusion–contraction matching, inhibits this activation. However, despite the reduction in p38 MAPK activation, SB203580 had no effect on contractility.

Although the phenomenon of myocardial hibernation is increasingly recognized, relatively little is known about the cellular processes that mediate this adaptive process. This is largely attributable to the presumed chronicity of hibernation, which can be difficult to reproduce experimentally, and the lack of a universally accepted animal model [16]. To this end, an NHLBI workshop has recommended the generation of appropriate small animal models of hibernation with high reproducibility, while recognizing that no single animal model may be appropriate to answer all the relevant questions [17].

Left ventricular dysfunction induced by low coronary flow, with perfusion–contraction coupling, has been termed short-term hibernation [18]. It was our aim to simulate short-term hibernation using low-flow perfusion. The isolated mouse heart adapted with perfusion–contraction coupling, while maintaining a contractile reserve. These features characterize hibernation [16].

The hallmark of hibernation is that the myocardial dysfunction is, at least in part, reversible [16]. Complete reversibility is unusual since affected myocardium usually contains scar [10,19]. In support of our findings, the reserve for augmentation of contractility with increased [Ca] is well recognized [16,20,21] and confirms the presence of contractile reserve in our model. Short-term hibernation is characterized by the absence of necrosis and animal models have shown greater functional recovery than the 35% seen here following reperfusion [22]. The brevity of the protocol, the hiatus in metabolic data, the lack of full functional recovery and the presence of infarction in the current study preclude the validation of this as a model of true hibernation and suggest instead, that this is a model of mixed reversible and irreversible myocardial injury rather than pure hibernation. However, the results reflect the modest recovery in systolic function seen in patients following revascularization (~12% in most series) [23,24], and our infarct size of 15% correlates with the extent of fibrosis in biopsy specimens of hibernating human myocardium, where the threshold amount of fibrosis differentiating myocardium with, from that without, recovery following revascularization is 17–35% [25,26].

The reduction in infarct size with early but not delayed administration of SB203580 would indicate that p38 MAPK activation soon after the onset of ischemia determines resulting infarct size. Similar cardioprotection was seen when SB203580 was administered prior to ischemia in rat neonatal cardiac myocytes [27], isolated rat [28] and rabbit hearts [29] and in an in vivo porcine model [30]. However, in contrast to our study, all bar one [27] of these studies gave the p38 MAPK inhibitor prior to the onset of ischemia. Furthermore, at the concentrations used in these studies (5–8 µM) [28,29], SB203580 may no longer be as specific for p38 MAPK inhibition as at concentrations ~1 µM and may also inhibit other kinases such as JNK [31,32]. Thus, although higher concentrations of SB203580 may have improved contractile dysfunction, we limited our study to examining the effects of SB203580 at concentrations specific for p38 MAPK inhibition. Our findings therefore advance the results of these earlier studies, by showing that even after the onset of ischemia, selective early blockade of p38 MAPK is cardioprotective.

Based on the literature regarding p38 MAPK activation in hibernating myocardium [9,10] and the negative inotropic effect associated with p38 MAPK activation in isolated cardiocytes [13], we had expected SB203580 to improve contractility. The most likely explanation for this negative result is that, despite its phosphorylation, p38 MAPK is not involved in mediating the reduction in contractility and is simply a bystander marker. However, the lack of effect of SB203580 could be attributable to other factors. Firstly, p38 MAPK phosphorylation may not reflect activation state [32]. In cell lines, SB203580 was shown to block the catalytic activity of p38 MAPK but not its activation by upstream MAPK kinase [33]. Furthermore, inhibition of p38 MAPK with SB203580 was shown to block the phosphorylation of downstream HSP27, without inhibiting p38 MAPK phosphorylation [34], implying that activation is not always mirrored by phosphorylation status. Similarly, although in the current study p38 MAPK phosphorylation was not totally blocked by SB203580, particularly under moderate flow conditions, we achieved complete inhibition of p38 MAPK activation as demonstrated by the total lack of downstream HSP27 phosphorylation and it was this inhibition of p38 MAPK activation that we sought to investigate.

Secondly, SB203580 only acts on {alpha} and β isoforms of p38 MAPK [35], therefore the non-inhibited {gamma} and {delta} isoforms may continue to exert a negative inotropic effect. However, this is unlikely since the dual phosphorylation of all p38 MAPK isotypes was diminished by SB203580. We investigated the possibility that p38 MAPK, although involved, is an early effector of impaired contractility and that after a while, pathways downstream of p38 MAPK become autonomous, such that any subsequent inhibition of p38 MAPK is no longer able to augment contractility. The observed lack of effect of SB203580 on contractility when given during the early stages of reduced flow in the present study or even before the onset of lethal ischemia in an earlier study [14] make this hypothesis very unlikely.

In conclusion, in the isolated mouse heart subjected to reduced flow ischemia, impaired contractility was associated with p38 MAPK activation, but inhibition of p38 activation failed to improve contractility, despite demonstration of a contractile reserve.


   Acknowledgements
 
DA Gorog and AMN Kabir are supported by fellowships from the British Heart Foundation (fellowships FS/2001 016 and FS/2001 043, respectively).


   Notes
 
Time for primary review 20 days


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

  1. Rahimtoola S.H. A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation (1985) 72:V123–V135.[Medline]
  2. Raingeaud J., Gupta S., Rogers J.S., et al. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem. (1995) 270:7420–7426.[Abstract/Free Full Text]
  3. Guay J., Lambert H., Gingras-Breton G., Lavoie J.N., Huot J., Landry J. Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. J. Cell. Sci. (1997) 110(Pt 3):357–368.[Abstract]
  4. Bogoyevitch M.A., Gillespie-Brown J., Ketterman A.J., et al. Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circ. Res. (1996) 79:162–173.[Abstract/Free Full Text]
  5. Armstrong S.C., Delacey M., Ganote C.E. Phosphorylation state of hsp27 and p38 MAPK during preconditioning and protein phosphatase inhibitor protection of rabbit cardiomyocytes. J. Mol. Cell. Cardiol. (1999) 31:555–567.[CrossRef][Web of Science][Medline]
  6. Wang Y., Huang S., Sah V.P., et al. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J. Biol. Chem. (1998) 273:2161–2168.[Abstract/Free Full Text]
  7. Cain B.S., Meldrum D.R., Meng X., et al. p38 MAPK inhibition decreases TNF-alpha production and enhances postischemic human myocardial function. J. Surg. Res. (1999) 83:7–12.[CrossRef][Web of Science][Medline]
  8. Cook S.A., Sugden P.H., Clerk A. Activation of c-Jun N-terminal kinases and p38-mitogen-activated protein kinases in human heart failure secondary to ischaemic heart disease. J. Mol. Cell. Cardiol. (1999) 31:1429–1434.[CrossRef][Web of Science][Medline]
  9. Luss H., Neumann J., Schmitz W., Schulz R., Heusch G. The stress-responsive MAP kinase p38 is activated by low-flow ischemia in the in situ porcine heart. J. Mol. Cell. Cardiol. (2000) 32:1787–1794.[CrossRef][Web of Science][Medline]
  10. Behrends M., Schulz R., Post H., et al. Inconsistent relation of MAPK activation to infarct size reduction by ischemic preconditioning in pigs. Am. J. Physiol. Heart Circ. Physiol. (2000) 279:H1111–H1119.[Abstract/Free Full Text]
  11. Zheng M., Zhang S.J., Zhu W.Z., Ziman B., Kobilka B.K., Xiao R.P. Beta 2-adrenergic receptor-induced p38 MAPK activation is mediated by protein kinase A rather than by Gi or gbeta gamma in adult mouse cardiomyocytes. J. Biol. Chem. (2000) 275:40635–40640.[Abstract/Free Full Text]
  12. Liao P., Wang S.Q., Wang S., et al. p38 Mitogen-activated protein kinase mediates a negative inotropic effect in cardiac myocytes. Circ. Res. (2002) 90:190–196.[Abstract/Free Full Text]
  13. Liao P., Georgakopoulos D., Kovacs A., et al. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc. Natl. Acad. Sci. U. S. A. (2001) 98:12283–12288.[Abstract/Free Full Text]
  14. Schulz R., Belosjorow S., Gres P., Jansen J., Michel M.C., Heusch G. p38 MAP kinase is a mediator of ischemic preconditioning in pigs. Cardiovasc. Res. (2002) 55:690–700.[Abstract/Free Full Text]
  15. Saurin A., Pennington D., Raat N., Latchman D., Owen M., Marber M. Targeted disruption of the protein kinase C epsilon gene abolishes the infarct size reduction that follows ischaemic preconditioning of isolated buffer-perfused mouse hearts. Cardiovasc. Res. (2002) 55:672.[Abstract/Free Full Text]
  16. Heusch G. Hibernating myocardium. Physiol. Rev. (1998) 78:1055–1085.[Abstract/Free Full Text]
  17. Kloner R.A., Bolli R., Marban E., Reinlib L., Braunwald E. Medical and cellular implications of stunning, hibernation, and preconditioning: an NHLBI workshop. Circulation (1998) 97:1848–1867.[Free Full Text]
  18. Ross J. Jr. Myocardial perfusion–contraction matching. Implications for coronary heart disease and hibernation. Circulation (1991) 83:1076–1083.[Abstract/Free Full Text]
  19. Beanlands R.S., Ruddy T.D., deKemp R.A., et al. Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function. J. Am. Coll. Cardiol. (2002) 40:1735–1743.[Abstract/Free Full Text]
  20. Headrick J.P., Peart J., Hack B., Flood A., Matherne G.P. Functional properties and responses to ischaemia–reperfusion in Langendorff perfused mouse heart. Exp. Physiol. (2001) 86:703–716.[Abstract/Free Full Text]
  21. Heusch G., Post H., Michel M.C., Kelm M., Schulz R. Endogenous nitric oxide and myocardial adaptation to ischemia. Circ. Res. (2000) 87:146–152.[Abstract/Free Full Text]
  22. van Binsbergen X.A., van Emous J.G., Ferrari R., van Echteld C.J., Ruigrok T.J. Metabolic and functional consequences of successive no-flow and sustained low-flow ischaemia; a 31P MRS study in rat hearts. J. Mol. Cell. Cardiol. (1996) 28:2373–2381.[CrossRef][Web of Science][Medline]
  23. Ragosta M., Beller G.A., Watson D.D., Kaul S., Gimple L.W. Quantitative planar rest-redistribution 201Tl imaging in detection of myocardial viability and prediction of improvement in left ventricular function after coronary bypass surgery in patients with severely depressed left ventricular function. Circulation (1993) 87:1630–1641.[Abstract/Free Full Text]
  24. Shivalkar B., Maes A., Borgers M., et al. Only hibernating myocardium invariably shows early recovery after coronary revascularization. Circulation (1996) 94:308–315.[Abstract/Free Full Text]
  25. Depre C., Vanoverschelde J.L., Melin J.A., et al. Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. Am. J. Physiol. (1995) 268:H1265–H1275.[Web of Science][Medline]
  26. Nagueh S.F., Mikati I., Weilbaecher D., et al. Relation of the contractile reserve of hibernating myocardium to myocardial structure in humans. Circulation (1999) 100:490–496.[Abstract/Free Full Text]
  27. Mackay K., Mochly-Rosen D. An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J. Biol. Chem. (1999) 274:6272–6279.[Abstract/Free Full Text]
  28. Maulik N., Watanabe M., Zu Y.L., et al. Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts. FEBS Lett. (1996) 396:233–237.[CrossRef][Web of Science][Medline]
  29. Gysembergh A., Simkhovich B.Z., Kloner R.A., Przyklenk K. p38 MAPK activity is not increased early during sustained coronary artery occlusion in preconditioned versus control rabbit heart. J. Mol. Cell. Cardiol. (2001) 33:681–690.[CrossRef][Web of Science][Medline]
  30. Barancik M., Htun P., Strohm C., Kilian S., Schaper W. Inhibition of the cardiac p38-MAPK pathway by SB203580 delays ischemic cell death. J. Cardiovasc. Pharmacol. (2000) 35:474–483.[CrossRef][Web of Science][Medline]
  31. Clerk A., Sugden P.H. The p38-MAPK inhibitor, SB203580, inhibits cardiac stress-activated protein kinases/c-Jun N-terminal kinases (SAPKs/JNKs). FEBS Lett. (1998) 426:93–96.[CrossRef][Web of Science][Medline]
  32. Sugden P.H., Clerk A. "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ. Res. (1998) 83:345–352.[Free Full Text]
  33. Kumar S., Jiang M.S., Adams J.L., Lee J.C. Pyridinylimidazole compound SB 203580 inhibits the activity but not the activation of p38 mitogen-activated protein kinase. Biochem. Biophys. Res. Commun. (1999) 263:825–831.[CrossRef][Web of Science][Medline]
  34. Martin J.L., Avkiran M., Quinlan R.A., Cohen P., Marber M.S. Antiischemic effects of SB203580 are mediated through the inhibition of p38alpha mitogen-activated protein kinase: evidence from ectopic expression of an inhibition-resistant kinase. Circ. Res. (2001) 89:750–752.[Abstract/Free Full Text]
  35. Lee J.C., Kassis S., Kumar S., Badger A., Adams J.L. p38 mitogen-activated protein kinase inhibitors—mechanisms and therapeutic potentials. Pharmacol. Ther. (1999) 82:389–397.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Exp PhysiolHome page
M. E. Reichelt, L. Willems, B. A. Hack, J. N. Peart, and J. P. Headrick
Cardiac and coronary function in the Langendorff-perfused mouse heart model
Exp Physiol, January 1, 2009; 94(1): 54 - 70.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
C. Doucet, S. Milin, F. Favreau, T. Desurmont, E. Manguy, W. Hebrard, Y. Yamamoto, G. Mauco, M. Eugene, V. Papadopoulos, et al.
A p38 mitogen-activated protein kinase inhibitor protects against renal damage in a non-heart-beating donor model
Am J Physiol Renal Physiol, July 1, 2008; 295(1): F179 - F191.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Jacquet, Y. Nishino, S. Kumphune, P. Sicard, J. E. Clark, K. S. Kobayashi, R. A. Flavell, J. Eickhoff, M. Cotten, and M. S. Marber
The Role of RIP2 in p38 MAPK Activation in the Stressed Heart
J. Biol. Chem., May 2, 2008; 283(18): 11964 - 11971.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gorog, D. A
Right arrow Articles by Marber, M. S
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gorog, D. A
Right arrow Articles by Marber, M. S
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?