H2O2-induced secretion of tumor necrosis factor-α evokes apoptosis of cardiac myocytes through reactive oxygen species-dependent activation of p38 MAPK
P38 mitogen-activated protein kinases (p38 MAPK) and tumor necrosis factor-α (TNF-α) play important roles in oxidative stress-induced apoptosis in cardiac myocytes. However, the regulation and functional role of cross-talk between p38 MAPK and TNF-α pathways have not yet been fully characterized in cardiac myocytes. In this study, we found that inhibition of p38 MAPK with SB-203580 (SB) reduced H2O2-stimulated secretion of TNF-α, whereas pre-activation of p38 MAPK with sodium arsenite (SA) enhanced H2O2-stimulated secretion of TNF-α. In addition, pretreatment of cells with TNF-α increased basal and H2O2-stimulated p38 MAPK and apoptosis of cardiac myocytes, and p38 MAPK-associated apoptosis of cardiac myocytes induced by TNF-α was blocked by inhibition of p38 MAPK with SB. Finally, H2O2-induced apoptosis was attenuated by the inhibitors of p38 MAPK or reactive oxygen species (ROS), whereas it was enhanced by p38 MAPK agonist SA. These results suggest that H2O2-induced secretion of TNF-α increases apoptosis of cardiac myocytes through ROS-dependent activation of p38 MAPK. This may represent a novel mechanism that TNF-α partly interplays with p38 MAPK pathways during oxidative stress-modulated apoptosis in cardiac myocytes.
Keywordsp38 mitogen-activated protein kinases Tumor necrosis factor-α Reactive oxygen species Apoptosis
We thank Dr Chen for his excellent technical assistance. This work was supported by the grant from Natural Science fund of Hubei Province (2009CDB244).
Conflict of interest
The authors state no conflict of interest.
- Kulisz A, Chen NF, Chandel NS, Shao ZH, Schumacker PT (2002) Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes. Am J Physiol Lung Cell Mol Physiol 282:L1324–L1329Google Scholar
- Li XN, Rong YY, Zhang M, Wang XL, LeMaire SA, Coselli JS, Zhang Y, Shen YH (2009) Up-regulation of thioredoxin interacting protein (Txnip) by p38 MAPK and FOXO1 contributes to the impaired thioredoxin activity and increased ROS in glucose-treated endothelial cells. Biochem Biophys Res Commun 381:660–665CrossRefGoogle Scholar
- Liu QH, Hofmann PA (2003) Modulation of protein phosphatase 2a by adenosine A(1) receptors in cardiomyocytes: role for p38 MAPK. Am J Physiol Heart Circ Physiol 285:H97–H103Google Scholar
- Meldrum KK, Meldrum DR, Hile KL, Yerkes EB, Ayala A, Cain MP, Rink RC, Casale AJ, Kaefer MA (2001) p38 MAPK mediates renal tubular cell TNF-alpha production and TNF-alpha-dependent apoptosis during simulated ischemia. Am J Physiol Cell Physiol 281:C563–C570Google Scholar
- Tomomi O, Toshio N, Hiroshi W, Atsuhiko T, Katsuhisa M, Koji I, Toshinao T, Motohiro G, Yoko M, Noritaka Y, Hiroshi A, Akiyoshi U, Shin T, Issei K (2007) Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo. J Cell Biol 176:329–341CrossRefGoogle Scholar
- Wang T, Chiang ET, Moreno-Vinasco L, Lang GD, Pendyala S, Samet JM, Geyh AS, Breysse PN, Chillrud SN, Natarajan V, Garcia JGN (2010) Particulate matter disrupts human lung endothelial barrier integrity via ROS- and p38 MAPK-dependent pathways. Am J Respir Cell Mol Biol 42:442–449CrossRefGoogle Scholar
- Yamamoto T, Yuyama K, Yamamoto H (2006) Low concentrations of nitric oxide (NO) induced cell death in PC12 cells through activation of p38 mitogen-activated protein kinase (p38 MAPK) but not via extracellular signal-regulated kinases (ERK1/2) or c-Jun N-terminal protein kinase (JNK). Neurosci Lett 392:170–173CrossRefGoogle Scholar