Inflame my heart (by p38-MAPK).

Although many studies have explored the stimuli which promote hypertrophic growth or death in cardiac myocytes and the signaling pathways which they activate, the mechanisms by which these pathways promote the pathophysiological responses are still obscure. The mitogen-activated protein kinase (MAPK) cascades (in which MAPKs are phosphorylated and activated by upstream MAPK kinases [MKKs] which are, in turn, phosphorylated and activated by MKK kinases [MKKKs]) were identified in the earlyto mid-1990s as potentially key regulatory pathways in cardiac myocyte pathophysiology.1,2 The principal MAPKs investigated in cardiac myocytes are the extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNKs), and p38-MAPKs. ERK1/2 are potently activated by hypertrophic stimuli, whereas JNKs and p38MAPKs are potently activated by cellular stresses (eg, oxidative stress). However, there is cross-talk such that JNKs and p38-MAPKs are activated by hypertrophic stimuli and ERK1/2 are activated by cellular stresses, and the contribution of each pathway to the overall cardiac myocyte response is not entirely clear. MAPKs phosphorylate a number of known transcription factors to alter their transactivating activities thus, presumably, influencing gene expression to elicit the cellular response.3 Nevertheless, the immediate consequences (ie, the transcription factors which are phosphorylated) and downstream consequences (ie, genes with altered expression) of MAPK signaling in the heart or specifically in cardiac myocytes are still largely unknown. To start to address this issue for the p38-MAPK pathway in the (rat) heart (Figure ), Tenhunen et al4 directly injected adenoviruses encoding wild-type (WT) p38-MAPK together with a mutated constitutively-activated (CA) upstream kinase (MKK3b) into the heart. The effects of stimulating p38-MAPK signaling on global gene expression in the left ventricle (assessed by microarray analysis), and cardiac function and pathology are reported. At 3 days, gene expression profiling identified a number of changes in gene expression, most notably in genes encoding proteins which regulate cell cycle progression or which are involved in inflammation. By 7 days, the hearts were noticeably fibrotic and contained many inflammatory cells. There was no evidence of cardiac myocyte hypertrophy. Initially, these results may perhaps seem surprising, given that p38-MAPK signaling in heart is usually considered in the context of cardiac myocyte hypertrophy or cytoprotection/apoptosis.2,5 However, in the historical perspective of p38-MAPK signaling in inflammation and allowing for the methodology used in the study, the responses are not necessarily entirely unexpected.