Inhibition of p38 reduces myocardial infarction injury in the mouse but not pig after ischemia-reperfusion

Dept. of Pediatrics, Cincinnati Children's Hospital Medical Center, Univ. of Cincinnati, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 01/2006; 289(6):H2747-51. DOI: 10.1152/ajpheart.01280.2004
Source: PubMed


The MAPK family member p38 is activated in the heart after ischemia-reperfusion (I/R) injury. However, the cardioprotective vs. proapoptotic effects associated with p38 activation in the heart after I/R injury remain unresolved. Another issue to consider is that the majority of past studies have employed the rodent as a model for assessing p38's role in cardiac injury vs. protection, while the potential regulatory role in a large animal model is even more uncertain. Here we performed a parallel study in the mouse and pig to directly compare the extent of cardiac injury after I/R at baseline or with the selective p38 inhibitor SB-239063. Infusion of SB-239063 5 min before ischemia in the mouse prevented ischemia-induced p38 activation, resulting in a 25% reduction of infarct size compared with vehicle-treated animals (27.9 +/- 2.9% vs. 37.5 +/- 2.7%). In the pig, SB-239063 similarly inhibited myocardial p38 activation, but there was no corresponding effect on the degree of infarction injury (43.6 +/- 4.0% vs. 41.4 +/- 4.3%). These data suggest a difference in myocardial responsiveness to I/R between the small animal mouse model and the large animal pig model, such that p38 activation in the mouse contributes to acute cellular injury and death, while the same activation in pig has no causative effect on these parameters.

Download full-text


Available from: Timothy O'Neill, Aug 20, 2015
  • Source
    • "For example, genes known to cause heart failure in the mouse may not cause the same disease phenotype in humans [7] or cause irrelevant undesired effects [8] [9], and drugs shown to have cardiotherapeutic effects in mice [10] can give rise to fatal consequences in humans [11]. Furthermore, cardiovascular data from mice often do not correlate with data from large animal models [12], and important species differences exist even between more closely related species, such as mice and rats [13], and even among different strains of the same species [14]. All of these effects are confounded by factors such as sex and age [15] [16] as well as laboratory conditions [17] and even animal husbandry practices [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure remains a leading cause of death and it is a major cause of morbidity and mortality affecting tens of millions of people worldwide. Despite decades of extensive research conducted at enormous expense, only a handful of interventions have significantly impacted survival in heart failure. Even the most widely prescribed treatments act primarily to slow disease progression, do not provide sustained survival advantage, and have adverse side effects. Since mortality remains about 50% within five years of diagnosis, the need to increase our understanding of heart failure disease mechanisms and development of preventive and reparative therapies remains critical. Currently, the vast majority of basic science heart failure research is conducted using animal models ranging from fruit flies to primates; however, insights gleaned from decades of animal-based research efforts have not been proportional to research success in terms of deciphering human heart failure and developing effective therapeutics for human patients. Here we discuss the reasons for this translational discrepancy which can be equally attributed to the use of erroneous animal models and the lack of widespread use of human-based research methodologies and address why and how we must position our own species at center stage as the quintessential animal model for 21(st) century heart failure research. If the ultimate goal of the scientific community is to tackle the epidemic status of heart failure, the best way to achieve that goal is through prioritizing human-based, human-relevant research.
    Full-text · Article · Nov 2015 · American Journal of Translational Research
  • Source
    • "During synthesis of a different compound, SB239063, it was discovered that methylation of the nitrogen in the imidizole group greatly improved the drug's bioavailability (Liverton et al 1999). The resulting inhibitor was shown to reduce myocardial infarction in the mouse (Kaiser et al 2005). In addition, use in rats and guinea pigs demonstrates that SB239063 effectively blocks p38 signaling in lung tissue when delivered intragrastrically before and after lipopolysaccharide inhalation challenge (Underwood et al 2000), demonstrating that this compound has substrate effi cacy in the lung. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Studies examining the cellular mechanisms of inflammation and protease production in the lung tissue and airways of COPD patients have shed light on the important role of kinase-based signaling cascades. These pathways can be activated by environmental stimuli such as tobacco smoke, and by endogenous signals such as cytokines, growth factors, and inflammation-derived oxidants. The three most widely characterized cascades are those directed by the classical mitogen activated protein (MAP) kinase (ERK1/2), stress activated protein kinase/c-Jun N-terminal protein kinase, and p38 enzymes. These phosphorylation cascades transmit and amplify extracellular, receptor-mediated signals through the cytoplasm of the cell to activate nuclear transcription factors which bind and induce expression of target genes. The result is tight control of diverse cellular events, and rapid responses to external stimuli. However, recent research suggests that constitutive or aberrant activation of MAP kinases contributes to several COPD-associated phenotypes, including mucus overproduction and secretion, inflammation, cytokine expression, apoptosis, T cell activation, matrix metalloproteinase production, and fibrosis. This review explores the biological functions of the MAP kinase pathways in the pathogenesis of COPD, their activation by cigarette smoke, and discusses the potential role of MAP kinase inhibitors in COPD therapy.
    Full-text · Article · Feb 2006 · International Journal of COPD
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Es wurden die Effekte einer Blockade von p38 MAPK durch SB 239063 über einen Zeitraum von 10 Wochen nach Myokardinfarzierung am Tiermodell der Ratte untersucht. P38 MAPK, ein Signaltransduktionsmolekül mit 4 Isoformen, das in den Zellzyklus, Zelldifferenzierung, Zelltod, Proteinsynthese und Gentranskription eingreift, kommt kardial eine zentrale Bedeutung für die Entstehung der kardiomyozytären Hypertrophie und Apoptose zu. Die ermittelten Daten zeigen eine indifferente und zum Teil negative Auswirkung von SB 239063 bei chronischer Gabe nach Myokardinfarzierung auf das kardiale Remodeling und die Herzfunktion, hingegen einen positiven Effekt auf das Endothel. The effects of the inhibition of p38 MAPK through SB 239063 over a 10 week period after myocardial infarction were examined in the rat model. P38 MAPK, a signal transduction molecule with 4 isoforms, which regulates cell cycle, cell differentiation, cell death, protein synthesis and gene transcription, has a central role in myocardial hypertrophy an apoptosis. The acquired data show an indifferent and partly negative effect of SB 239063 with chronic administration after myocardial infarction on myocardial remodeling and heart function, but a positive effect on the endothelium.
    Preview · Article ·
Show more