© 2000 American Heart Association, Inc.
Editorials |
Role of p38 Mitogen-Activated Protein Kinases in Preconditioning
A Detrimental Factor or a Protective Kinase?
From the Departments of Medicine/Division of Cardiology and Physiology and Biophysics (P.P.), University of Louisville, and Jewish Hospital Heart and Lung Institute (P.P.), Louisville, Ky; and Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences (E.M.), Research Triangle Park, NC.
Correspondence to Peipei Ping, PhD, 570 South Preston St, 1st Floor North, Room 122, Cardiology Research, University of Louisville, Louisville, KY 40202-1783. E-mail ping{at}ntr.net
Key Words: cardioprotection • kinases • signal transduction
 |
Introduction |
|---|
 Top Introduction References |
|---|
Preconditioning, the phenomenon whereby brief episodes of ischemia or pharmacological agents protect the myocardium against subsequent ischemic injury, consists of an early and a late phase.1 The early phase develops immediately and disappears within 1 to 2 hours of ischemic preconditioning stimulus, whereas the late phase, also known as the "second window" of protection, becomes manifest after 12 to 24 hours and lasts for 3 to 4 days. An understanding of the signaling mechanisms that trigger and mediate this cardioprotective phenomenon would have vast physiological and pathological implications. Accordingly, many recent studies have focused on the characterization and delineation of the signal transduction pathways (molecules) underlying the development and manifestation of both the early and late phases of preconditioning. The general hypothesis is that the preconditioning stimulus will induce the activation of a cascade of stress-responsive kinases, which in turn transduce the stress signal into the generation of a protective protein or activation of a protective kinase. In this context, the p38 mitogen-activated protein kinases (MAPKs), a family of stress-activated MAPKs,2 3 have been examined as the candidate kinases during preconditioning.
In this issue of Circulation Research, Dana et al4 report that the adenosine A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA) induces a late phase of preconditioning in rabbit hearts. Twenty-four hours after the transient activation of the adenosine A1 receptor, the myocardium exhibited a significant rise in the activity of p38 MAPK. The increased p38 MAPK activity was completely abolished when the infarct-sparing effect of CCPA was abrogated by either the protein kinase C (PKC) inhibitor chelerythrine or the tyrosine kinase inhibitor lavendustin A. This is a very provocative study, and it is also the first to demonstrate activation of the p38 MAPK 24 hours after preconditioning. The data are compatible with the hypothesis that p38 MAPKs may mediate the protective signaling pathways or function as protective kinases during the late phase of pharmacological preconditioning. However, this conclusion is based on the correlation between activation of p38 MAPK and protection. Before the role of p38 MAPK in late preconditioning can be definitely established, it is necessary to show that the inhibition of p38 MAPK blocks the protection. If activation of p38 MAPKs is a necessary signaling event for the protection to manifest on day 2, then inhibition of this kinase will lead to the abrogation of late preconditioning.
The role of the p38 MAPK signaling pathway in the early phase of preconditioning has been more extensively investigated.5 6 7 8 9 10 11 However, the published observations are inconsistent, and the role of p38 MAPKs in early preconditioning seems to be controversial. The two lines of studies performed thus far have sought to determine (1) whether preconditioning induces the activation of p38 MAPKs and (2) whether inhibition of p38 MAPKs abrogates the cardioprotective effect. Unfortunately, both have yielded conflicting results. In the first line of studies, it remains uncertain whether ischemia/reperfusion induces sustained activation of p38 MAPKs. Ischemia stimulus has been shown to induce activation of p38 MAPKs.5 6 Furthermore, ischemic preconditioning activates MAPKAPK2, the downstream signaling substrate of p38 MAPK,5 6 demonstrating that activation of the p38 MAPK signaling cascade, not just one element of the MAPK module, is part of the signaling events involved in preconditioning. Although activation of p38 MAPK has been confirmed in several studies,7 8 12 13 the temporal aspects of the activation have been a point of debate. Several studies7 12 13 have reported that activation of p38 MAPKs during ischemia is transient and does not correlate with the preconditioning effect, thereby questioning the functional significance of this observation. In the second line of studies, at the center of the controversy are data obtained using the specific p38 MAPK inhibitors (SB 203580 or SB 202190). Inhibition of p38 MAPK was shown to completely block the cardioprotective phenomenon in several studies,5 6 8 indicating that activation of p38 MAPK is an essential signaling event in the genesis of preconditioning. In apparent contradiction to these findings, several recent studies9 10 11 report that SB 203580 and SB 202190 can function as cardioprotective compounds, ie, that they improve postischemic functional recovery,10 delay myocardial cell death,11 and precondition cardiac myocytes against simulated ischemia.9 These studies suggest that, far from playing a protective role, activation of the stress kinase p38 MAPK may be detrimental to the heart and inhibition of this stress-activated kinase will protect the myocardium.
What could be the reasons for the discrepancies of these studies? One obvious explanation has to do with the experimental models and animal species. The experimental models used to test the role of p38 MAPK are vastly different, ranging from isolated perfused rabbit hearts,6 rat hearts,5 10 and pig hearts,7 11 to cultured cardiac cells8 9 and biopsy tissue samples from human hearts.12 The preconditioning protocols differ among studies, and the endpoints examined are also different in each investigation. To a certain extent, these factors may have contributed to the conflicting observations. Nevertheless, a mechanism that is not conserved across species is arguably less significant than one that is manifest in multiple biological systems. The fact that the expression of p38 MAPKs is strikingly conserved from yeast to humans2 combined with the observation that the preconditioning phenomenon has been demonstrated in all species tested1 suggests a more fundamental mechanism that is common to all models.
Recent studies have demonstrated that the family of p38 MAPKs is
composed of at least 4 isoforms, namely, p38
, p38ß, p38
, and
p38
.2 3 Studies in cultured cells have shown that
individual isoforms of the p38 MAPK may possess distinct biological
functions.2 14 Thus, a second plausible explanation for
the p38 MAPK controversy may be the differential actions of individual
isoforms of the p38 MAPK family. One critical missing piece of the
puzzle in all of the above reports is the effect of preconditioning on
the activity of individual p38 MAPK isoforms and their corresponding
downstream substrates. Characterization of the myocardial expression of
all p38 MAPK isoforms and their downstream signaling targets would be
necessary prerequisites for these studies. For example, selective
activation of only one p38 isoform may result in an apparent lack of
activation of the entire p38 MAPK family, a phenomenon that has been
documented with the role of PKC isoforms in preconditioning. Indeed,
one of the most powerful arguments against a role of PKC in
preconditioning is the observation that total PKC activity did not
increase after a preconditioning stimulus.15 However, it
was found subsequently in rabbits that preconditioning induces
selective activation of only 2 of the 11 known PKC isoforms (
and
) and is insufficient to elevate total PKC
activity.16
The third possibility for the inconsistencies resides in the efficacy
and selectivity of the pyridinlimidazole compound SB 203580. Although
this agent has a potent effect on the activity of the p38 and p38ß
MAPKs, its efficacy for the p38 and p38 isoforms is
low.17 Moreover, at a higher concentration
(IC50=5 µmol/L), this compound will
inhibit the c-Jun N-terminal kinase (JNK) family of
MAPKs17 and phosphatidylinositol 3 (PI3) kinase/protein
kinase B,18 and both the JNK and PI3 kinases have been
shown to be recruited by ischemic
preconditioning.13 19 It is difficult to assess the
precise intracellular concentrations of this compound achieved in the
isolated-perfused heart models; however, it is highly likely that the
concentration of the inhibitor used may vary in different
studies. This may have contributed to the inconsistent findings
in the literature.
In summary, targeted activation or inhibition of individual p38 MAPK isoforms will be essential to provide conclusive evidence to either support or refute the role of p38 MAPKs in the early and late phases of preconditioning. The development of isoform-specific pharmacological inhibitors or transgenic mice expressing a cardiac-specific individual p38 MAPK isoform (in its active or trans-dominantly negative form) should provide important contributions to resolving this controversy.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
- Downey JM, Cohen MV. Signal transduction in ischemic preconditioning. Adv Exp Med Biol.. 1997;430:39–55.[Medline] [Order article via Infotrieve]
- Garrington TP, Johnson GL. Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol.1999;11:211–218.
-
Sugden PH, 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] - Dana A, Skarli M, Papakrivopoulou J, Yellon DM. Adenosine A1 receptor induced delayed preconditioning in rabbits: induction of p38 mitogen-activated protein kinase activation and Hsp27 phosphorylation via a tyrosine kinase– and protein kinase C–dependent mechanism. Circ Res. 2000; 86:989–997.
-
Maulik N, Yoshida T, Zu YL, Sato M, Banerjee A, Das
DK. Ischemic preconditioning triggers tyrosine kinase
signaling: a potential role for MAPKAP kinase 2. Am J
Physiol. 1998;275:H1857–H1864.
[Abstract/Free Full Text] - Nakano A, Baines CP, Kim SO, Pelech SL, Downey JM, Cohen MV, Critz SD. Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart: evidence for involvement of p38 MAPK. Circ Res.2000;86:144–151.
- Behrends M, Schulz R, Post H, Alexandrow A, Belosjorow S, Michel MC, Heusch G. Inconsistent relation of MAP kinase activation to infarct size reduction by ischemic preconditioning in the porcine heart in situ. Am J Physiol. In press.
- Armstrong SC, Delacey M, Ganote CE. 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.[Medline] [Order article via Infotrieve]
-
Saurin AT, Heads RJ, Foley C, Wang Y, Marber MS.
Inhibition of p38 activation may underlay protection in a
surrogate model of ischemic preconditioning.
Circulation. 1999;100(suppl I):I-492. Abstract.
- Schneider S, Hou J, London RE, Steenbergen C, Murphy E. Inhibition of p38 MAP kinase reduces ischemic injury and does not block the protective effects of preconditioning. J Mol Cell Cardiol. 1999;31:A43. Abstract.
- 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.
-
Talmor D, Applebaum A, Rudich A, Shapira Y, Tirosh A.
Activation of mitogen-activated protein kinases in human heart
during cardiopulmonary bypass. Circ Res. 2000;86:1004–1007.
[Abstract/Free Full Text] - Ping P, Zhang J, Huang S, Cao X, Tang X, Li R, Zheng Y, Qiu Y, Clerk A, Sugden P, Han J, Bolli R. PKC-dependent activation of p46/p54 JNKs during ischemic preconditioning in conscious rabbits. Am J Physiol.1999; 277:1771–1785.
-
Wang Y, Su B, Sah VP, Brown JH, Han J, Chien KR.
Cardiac hypertrophy induced by mitogen-activated
protein kinase 7, a specific activator for c-Jun
NH2-terminal kinase in ventricular muscle cells.
J Biol Chem. 1998;273:5423–5426.
[Abstract/Free Full Text] -
Przyklenk K, Sussman MA, Simkhovich BZ, Kloner RA. Does
ischemic preconditioning trigger translocation of protein
kinase C in the canine model? Circulation. 1995;92:1546–1557.
[Abstract/Free Full Text] -
Ping P, Zhang J, Qiu Y, Tang X, Manchikalapudi S,
Cao X, Bolli R. Ischemic preconditioning induces selective
translocation of protein kinase C isoforms and in the
heart of conscious rabbits without subcellular redistribution of total
protein kinase C activity. Circ Res. 1997;81:404–414.
[Abstract/Free Full Text] - Lee JC, Kassis S, Kumar S, Badger A, Adams JL. p38 Mitogen-activated protein kinase inhibitors: mechanisms and therapeutic potentials. Pharmacol Ther. 1999;82:389–397.[Medline] [Order article via Infotrieve]
-
Lali FV, Hunt AE, Turner SJ, Foxwell BM. The pyridinyl
imidazole inhibitor SB 203580 blocks
phosphoinositide-dependent protein kinase activity,
protein kinase B phosphorylation, and retinoblastoma
hyperphosphorylation in interleukin-2-stimulated T
cells independently of p38 mitogen-activated protein kinase.
J Biol Chem. 2000;275:7395–7402.
[Abstract/Free Full Text] - Tong H, Chen W, London RE, Murphy E, Steenbergen C. Phosphoinositide-3-kinase (PI3K) is involved in preconditioning. J Mol Cell Cardiol. 1999;31:A19. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  S. Jacquet, E. Zarrinpashneh, A. Chavey, A. Ginion, I. Leclerc, B. Viollet, G. A. Rutter, L. Bertrand, and M. S. Marber The relationship between p38 mitogen-activated protein kinase and AMP-activated protein kinase during myocardial ischemia Cardiovasc Res, December 1, 2007; 76(3): 465 - 472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. C. Zhao, G. Cheng, L. X. Zhang, Y. T. Tseng, and J. F. Padbury Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury Cardiovasc Res, December 1, 2007; 76(3): 473 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Hochhauser, D. Leshem, O. Kaminski, Y. Cheporko, B. A. Vidne, and A. Shainberg The protective effect of prior ischemia reperfusion adenosine A1 or A3 receptor activation in the normal and hypertrophied heart Interactive CardioVascular and Thoracic Surgery, June 1, 2007; 6(3): 363 - 368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Wall, J. Wei, M. Ly, P. Belmont, J. J. Martindale, D. Tran, J. Sun, W. J. Chen, W. Yu, P. Oeller, et al. Alterations in oxidative phosphorylation complex proteins in the hearts of transgenic mice that overexpress the p38 MAP kinase activator, MAP kinase kinase 6 Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2462 - H2472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Hausenloy and D. M. Yellon Survival kinases in ischemic preconditioning and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 240 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Okada, H. Otani, Y. Wu, S. Kyoi, C. Enoki, H. Fujiwara, T. Sumida, R. Hattori, and H. Imamura Role of F-actin organization in p38 MAP kinase-mediated apoptosis and necrosis in neonatal rat cardiomyocytes subjected to simulated ischemia and reoxygenation Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2310 - H2318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sumida, H. Otani, S. Kyoi, T. Okada, H. Fujiwara, Y. Nakao, M. Kido, and H. Imamura Temporary blockade of contractility during reperfusion elicits a cardioprotective effect of the p38 MAP kinase inhibitor SB-203580 Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2726 - H2734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Martindale, J. A. Wall, D. M. Martinez-Longoria, P. Aryal, H. A. Rockman, Y. Guo, R. Bolli, and C. C. Glembotski Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo J. Biol. Chem., January 7, 2005; 280(1): 669 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kaiser, O. F. Bueno, D. J. Lips, P. A. Doevendans, F. Jones, T. F. Kimball, and J. D. Molkentin Targeted Inhibition of p38 Mitogen-activated Protein Kinase Antagonizes Cardiac Injury and Cell Death Following Ischemia-Reperfusion in Vivo J. Biol. Chem., April 9, 2004; 279(15): 15524 - 15530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, R. Rajashree, Q. Liu, and P. Hofmann Acute p38 MAPK activation decreases force development in ventricular myocytes Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2578 - H2586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tanno, R. Bassi, D. A. Gorog, A. T. Saurin, J. Jiang, R. J. Heads, J. L. Martin, R. J. Davis, R. A. Flavell, and M. S. Marber 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., August 8, 2003; 93(3): 254 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. H. Patel, R. M. Fryer, E. R. Gross, R. A. Bundey, A. K. Hsu, M. Isbell, L. O.V. Eusebi, R. V. Jensen, S. R. Gullans, P. A. Insel, et al. 12-Lipoxygenase in Opioid-Induced Delayed Cardioprotection: Gene Array, Mass Spectrometric, and Pharmacological Analyses Circ. Res., April 4, 2003; 92(6): 676 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Morrison, H. E. Hoover, D. J. Thuerauf, and C. C. Glembotski Mimicking Phosphorylation of {alpha}B-Crystallin on Serine-59 Is Necessary and Sufficient to Provide Maximal Protection of Cardiac Myocytes From Apoptosis Circ. Res., February 7, 2003; 92(2): 203 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Weinbrenner, M. Nelles, N. Herzog, L. Sarvary, and R. H Strasser Remote preconditioning by infrarenal occlusion of the aorta protects the heart from infarction: a newly identified non-neuronal but PKC-dependent pathway Cardiovasc Res, August 15, 2002; 55(3): 590 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yue, Q. Qin, M. V Cohen, J. M Downey, and S. D Critz The relative order of mKATP channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart Cardiovasc Res, August 15, 2002; 55(3): 681 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kulisz, N. Chen, N. S. Chandel, Z. Shao, and P. T. Schumacker Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes Am J Physiol Lung Cell Mol Physiol, June 1, 2002; 282(6): L1324 - L1329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Liao, S.-Q. Wang, S. Wang, M. Zheng, M. Zheng, S.-J. Zhang, H. Cheng, Y. Wang, and R.-P. Xiao p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes Circ. Res., February 8, 2002; 90(2): 190 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-M. Oh, D. H. Hahm, I.-H. Kim, and S.-Y. Choi Human Neutrophil Lactoferrin trans-Activates the Matrix Metalloproteinase 1 Gene through Stress-activated MAPK Signaling Modules J. Biol. Chem., November 2, 2001; 276(45): 42575 - 42579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch Signal transduction of ischemic preconditioning Cardiovasc Res, November 1, 2001; 52(2): 181 - 198. [Full Text] [PDF]
|
|
|
|
|
|
R. M. Fryer, H. H. Patel, A. K. Hsu, and G. J. Gross Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1184 - H1192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Tekin, L. Xi, T. Zhao, M. I. Tejero-Taldo, S. Atluri, and R. C. Kukreja Mitogen-activated protein kinases mediate heat shock-induced delayed protection in mouse heart Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H523 - H532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yue, M. Krenz, M. V. Cohen, J. M. Downey, and S. D. Critz Menadione mimics the infarct-limiting effect of preconditioning in isolated rat hearts Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H590 - H595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H. Wang Roads to Survival : Insulin-Like Growth Factor-1 Signaling Pathways in Cardiac Muscle Circ. Res., March 30, 2001; 88(6): 552 - 554. [Full Text] [PDF]
|
|
|
|
|
|
S. Schneider, W. Chen, J. Hou, C. Steenbergen, and E. Murphy Inhibition of p38 MAPK {alpha}/{beta} reduces ischemic injury and does not block protective effects of preconditioning Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H499 - H508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bolli The Late Phase of Preconditioning Circ. Res., November 24, 2000; 87(11): 972 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Han, H. Wang, H. Long, S. Nattel, and Z. Wang Oxidative Preconditioning and Apoptosis in L-cells. ROLES OF PROTEIN KINASE B AND MITOGEN-ACTIVATED PROTEIN KINASES J. Biol. Chem., July 6, 2001; 276(28): 26357 - 26364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Liao, S.-Q. Wang, S. Wang, M. Zheng, M. Zheng, S.-J. Zhang, H. Cheng, Y. Wang, and R.-P. Xiao p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes Circ. Res., February 8, 2002; 90(2): 190 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Martin, M. Avkiran, R. A. Quinlan, P. Cohen, and M. S. Marber Antiischemic Effects of SB203580 Are Mediated Through the Inhibition of p38{alpha} Mitogen-Activated Protein Kinase: Evidence From Ectopic Expression of an Inhibition-Resistant Kinase Circ. Res., October 26, 2001; 89(9): 750 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. C. Zhao, M. M. Taher, K. C. Valerie, and R. C. Kukreja p38 Triggers Late Preconditioning Elicited by Anisomycin in Heart: Involvement of NF-{kappa}B and iNOS Circ. Res., November 9, 2001; 89(10): 915 - 922. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||