PRECLINICAL STUDY: EDITORIAL COMMENT
p38 Mitogen-Activated Protein Kinase
A Future Target for Heart Failure Therapy?*
Risto Kerkela, MD, PhD and
Thomas Force, MD*
Center for Translational Medicine, Jefferson Medical College, Philadelphia, Pennsylvania.
* Reprint requests and correspondence: Dr. Thomas Force, Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, College Building Room 316, Philadelphia, Pennsylvania 19107. (Email: thomas.force{at}jefferson.edu).
In this issue of the Journal, Bellahcene et al. (1) report that tumor necrosis factor-alpha (TNF- )-induced depression of contractile function of the heart is mediated by a specific intracellular signaling pathway, the p38 mitogen-activated protein kinase (MAPK) pathway. Why is this important? Numerous studies have identified proinflammatory cytokines, including TNF-, as potential mediators of the progression of congestive heart failure (CHF). Levels of TNF- were first found to be increased in patients with markedly advanced heart failure and later found to correlate with prognosis (2,3). Following these initial discoveries, Mann et al. (4) and Feldman et al. (5), working with mouse models over-expressing either TNF- or its receptors in the heart, respectively, found that activation of TNF- signaling recreated many of the key pathologies of heart failure: myocyte hypertrophy, remodeling of the extracellular matrix with increased fibrosis, and apoptosis. In addition, of direct relevance to Bellahcene et al. (1), injection of TNF- produced a deleterious hemodynamic response similar to that seen in septic shock (6), and administration of TNF to volunteers depressed left ventricular function, resulting in hypotension (7). These and many other studies raised the hypothesis that TNF- played a significant role in the progression of heart failure.
This hypothesis was tested in recent clinical trials in patients with heart failure with agents targeting TNF-, either by a decoy approach (i.e., preventing interaction of TNF- with the native receptor; etanercept), or by neutralizing TNF- with an intravenously administered monoclonal antibody (infliximab). Results of the trials were, to say the least, disappointing, showing either no benefit or worsened outcomes (8). At the moment, agents targeted to neutralize TNF- are in use for rheumatoid arthritis, inflammatory bowel disease, and psoriasis, but physicians are recommended to exercise caution in using etanercept in patients with CHF, and use of greater than a 5 mg/kg dose of infliximab is contraindicated in patients with New York Heart Association functional class III/IV CHF.
There are several possible explanations for the lack of benefit of these agents in the treatment of heart failure. These include complement fixation on the myocyte cell membrane following infliximab administration or a stabilizing effect of etanercept on TNF-, leading to elevated circulating levels of the cytokine (8). Alternatively, progression of CHF may be due to multiple cytokines and not just TNF-, because, for example, interleukin (IL)-6 levels are also highly correlated with a poor prognosis (3). Another possibility is that TNF- may have beneficial as well as deleterious effects on the heart. Supporting this concept, studies in mice with both TNF receptors knocked out showed that ischemic injury was increased (9).
Tumor necrosis factor- activates 4 key pathways in the cell (Fig. 1). These are: 1) a proapoptotic pathway leading to activation of caspase 8; 2) the c-Jun-N-terminal kinase (JNK) pathway that enhances matrix remodeling and, if persistently activated, apoptosis; 3) the nuclear factor- B (NF-B) pathway, which indirectly (via JNK inhibition) and directly (via induction of antiapoptotic factors) suppresses apoptosis, thus serving as a counter-regulator; and 4) the p38 pathway which depresses contractility and enhances matrix remodeling and the inflammatory state. Therefore targeting specific pathways, in theory, might provide a more selective approach to treating heart failure than targeting TNF- signaling at the TNF-/TNF receptor level, because cytoprotective NF-B signaling would not be impaired yet the inflammatory state and matrix remodeling might be reduced and contractility improved. This, of course, is entirely speculative in the absence of any data in patients with heart failure.
p38 is a signaling molecule that has been exhaustively studied since its discovery almost 12 years ago. It is involved in multiple cellular processes in many types of cells, including inflammation, cell growth, and cell death. In the heart, p38 is activated by numerous pathologic stresses, including ischemia (and, to a lesser extent, reperfusion) and pressure overload, and activation of p38 has been observed in human hearts with advanced heart failure (10,11). Its role in regulating cardiac hypertrophy remains controversial (12), but studies employing both genetic and pharmacologic inhibition of p38 suggest it plays a key role in left ventricular extracellular matrix remodeling (12), in cell survival following ischemia-reperfusion (13,14), and, possibly, in post-myocardial infarction (MI) remodeling (15). These adverse effects are mediated, in part, via p38-regulated induction of inflammatory cytokines. This is accomplished in large part by p38-mediated activation of mitogen-activated protein kinase-activated protein kinase 2 (MK2), which increases levels of inflammatory cytokines by stabilizing their messenger ribonucleic acid and by enhancing translation (16). This creates a positive feedback loop wherein inflammatory cytokines lead to the activation of p38/MK2 which then increases levels of inflammatory cytokines (Fig. 1).
The first clear evidence that p38 activation produced negative inotropic effects in vivo was provided by Wang et al. (reviewed in reference 12). Subsequent studies in vitro showed that adenovirus-mediated gene transfer of an activated mutant of MKK3, a kinase that directly activates p38, led to decreased contractility, and, conversely, pharmacologic blockade of p38 enhanced contractility in cultured cardiac myocytes (17). Importantly, this study suggested that the negative inotropic effect of p38 is mediated by altering myofilament sensitivity to intracellular calcium concentration. The negative inotropic effects of p38 have since been confirmed in both in vitro and in vivo models.
Bellahcene et al. (1) now show that either genetic inhibition of p38, achieved by knocking out MKK3, an upstream activator of p38 (Fig. 1), or pharmacologic inhibition of p38 (with a small molecule inhibitor) attenuate TNF-–induced contractile depression in an isolated perfused mouse heart model (thereby eliminating contributions from the periphery, which can obviously be quite profound with TNF-). Importantly, they go even further down the pathway to demonstrate that knocking out the p38 target, MK2, also largely prevents the negative inotropic response induced by TNF-, although the authors point out that this could be due to the fact that MK2 knockout mice have reduced p38 levels in their hearts. Of note, whereas the current study focuses on early effects of TNF- on cardiac contractility, data from numerous in vitro and ex vivo studies concur that TNF- and other cytokines produce a negative inotropic response with early effects within 30 min and prolonged effects for up to 48 to 72 h (7). The mechanisms of the late effects are not known.
Most of the clinical trials of small molecule inhibitors of p38 target inflammatory diseases or multiple myeloma. Preclinical studies in models of cardiovascular diseases suggest that inhibition of p38 might have applications in ischemic diseases, including acute coronary syndromes (ACS), because, as noted, various strategies to block p38 (and MK2) activation in MI models were protective (13–15,18). Inhibitors of p38 are currently in clinical trials for treatment of stroke (SCIO323) and acute coronary syndrome (VX702). In the latter study, patients going to percutaneous coronary intervention were treated for 5 days with VX702 versus placebo. There was no increase in adverse events, and serum levels of C-reactive protein (CRP) were reduced by VX702, possibly consistent with an antiinflammatory effect in ACS. Intriguingly, CRP levels remained reduced 4 weeks after the drug had been stopped.
Is there any rationale for the use of p38 inhibitors in heart failure patients besides the fact that p38 activity is increased in the hearts of these patients (10,11)? We believe the answer to this question may be a very cautious "yes." In addition to studies supporting beneficial effects on contractile function and matrix remodeling in animal models, Kyoi et al. (19) recently reported that inhibition of p38 with either of 2 small molecule inhibitors, SB203580 and FR167653, reduced apoptosis, fibrosis, hypertrophy, and left ventricular dilatation and increased ejection fraction and left ventricular contractility in the cardiomyopathic hamster model. Of note, the proinflammatory effects of p38 are likely mediated by several inflammatory cytokines in addition to TNF-, including IL-1-ß and IL-6 which are hypothesized to play roles in progression of heart failure. Thus, if the anti-TNF- heart failure studies failed, in part, because cytokines in addition to TNF are involved, p38 inhibition might address that issue more effectively. To our knowledge, only 1 clinical trial of a p38 inhibitor in patients with heart failure has been initiated (with semapimod), but this trial was apparently stopped when the results of the TNF--targeted heart failure trials were reported. However, p38 inhibition, if able to be tolerated long term, may have the potential to not only increase contractility (1) but also to reduce matrix remodeling. Clearly, though, there is a need for much more preclinical work in this area before proceeding to trials in this complex and fragile patient population.
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Footnotes
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Supported by research funds from the National Institutes of Health (RO1 HL6737-1 and HL6168-8). Dr. Force received support for laboratory research from Vertex Pharmaceuticals in 2004.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Bellahcene M, Jacquet S, Cao XB, 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]2. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure N Engl J Med 1990;323:236-241.[Abstract] 3. Mann DL. Inflammatory mediators and the failing heartpast, present, and the foreseeable future. Circ Res 2002;91:988-998.[Abstract/Free Full Text] 4. Diwan A, Dibbs Z, Nemoto S, et al. Targeted overexpression of noncleavable and secreted forms of tumor necrosis factor provokes disparate cardiac phenotypes Circulation 2004;109:262-268.[Abstract/Free Full Text] 5. Higuchi Y, McTiernan CF, Frye CB, McGowan BS, Chan TO, Feldman AM. Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-alpha-induced cardiomyopathy Circulation 2004;109:1892-1897.[Abstract/Free Full Text] 6. Tracey KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin Science 1986;234:470-474.[Abstract/Free Full Text] 7. Prabhu SD. Cytokine-induced modulation of cardiac function Circ Res 2004;95:1140-1153.[Abstract/Free Full Text] 8. Mann DL. Targeted anticytokine therapy and the failing heart Am J Cardiol 2005;95:9C-16C.[CrossRef][Web of Science][Medline] 9. Kurrelmeyer KM, Michael LH, Baumgarten G, et al. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction Proc Natl Acad Sci U S A 2000;97:5456-5461.[Abstract/Free Full Text] 10. Cook SA, Sugden PH, 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] 11. Haq S, Choukroun G, Lim H, et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure Circulation 2001;103:670-677.[Abstract/Free Full Text] 12. Petrich BG, Wang Y. Stress-activated MAP kinases in cardiac remodeling and heart failure; new insights from transgenic studies Trends Cardiovasc Med 2004;14:50-55.[CrossRef][Web of Science][Medline] 13. Ma XL, Kumar S, Gao F, et al. Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion Circulation 1999;99:1685-1691.[Abstract/Free Full Text] 14. Shao Z, Bhattacharya K, Hsich E, et al. c-Jun N-terminal kinases mediate reactivation of Akt and cardiomyocyte survival after hypoxic injury in vitro and in vivo Circ Res 2006;98:111-118.[Abstract/Free Full Text] 15. Ren J, Zhang S, Kovacs A, Wang Y, Muslin AJ. Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction J Mol Cell Cardiol 2005;38:617-623.[CrossRef][Web of Science][Medline] 16. Gaestel M. MAPKAP kinases—MKs—two’s company, three’s a crowd Nat Rev Mol Cell Biol 2006;7:120-130.[CrossRef][Web of Science][Medline] 17. Liao P, Wang SQ, 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] 18. Shiroto K, Otani H, Yamamoto F, Huang CK, Maulik N, Das DK. MK2–/– gene knockout mouse hearts carry antiapoptotic signal and are resistant to ischemia reperfusion injury J Mol Cell Cardiol 2005;38:93-97.[CrossRef][Web of Science][Medline] 19. Kyoi S, Otani H, Matsuhisa S, et al. Opposing effect of p38 MAP kinase and JNK inhibitors on the development of heart failure in the cardiomyopathic hamster Cardiovasc Res 2005;69:888-898.
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