Attenuation of CHOP-mediated myocardial apoptosis in pressure-overloaded dominant negative p38α mitogen-activated protein kinase mice

Flori R. Sari, Bambang Widyantoro, Rajarajan A. Thandavarayan, Meilei Harima, Arun Lakshmanan, Shaosong Zhang, Anthony J. Muslin, Kenji Suzuki, Makoto Kodama, Kenichi Watanabe

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Abstract

Background/Aims: Pressure overload stimulation is known to elicit disturbances in the endoplasmic reticulum (ER), which leads to ER stress (ERS). p38 mitogen-activated protein kinase (MAPK) plays an important role in mediating apoptotic processes, however, the roles of this kinase in activating ERS-initiated apoptosis in pressure-overloaded hearts are largely unknown. Methods: We clarified the role of p38α MAPK in ERS-associated apoptosis by subjecting transgenic mice displaying cardiac specific dominant negative (DN) mutant p38α MAPK over-expression to seven day pressure overload. Results: Seven days pressure overload resulted in the same extent of cardiac hypertrophy and ERS in the wild-type (WT) and DN p38α mice compared with the sham mice. It also activated inositol-requiring enzyme (Ire)-1α and its downstream molecule, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2 in the WT and DN p38α mice compared with the sham mice. Interestingly, increased myocardial apoptosis and the up-regulation of CCAAT/enhancer binding protein homology protein (CHOP) expression compared with those in the sham mice were found in the aortic-banded WT mice, but not in the DN p38α mice. Conclusion: Partial inhibition of p38α protein blocked the activation of CHOP-mediated apoptotic processes during pressure overload by partially inhibiting signaling from the Ire-1α/TRAF2 to its down-stream molecule, CHOP.

Original languageEnglish
Pages (from-to)487-496
Number of pages10
JournalCellular Physiology and Biochemistry
Volume27
Issue number5
DOIs
Publication statusPublished - 27 Jun 2011
Externally publishedYes

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Keywords

  • Apoptosis
  • Endoplasmic reticulum stress
  • p38 MAPK
  • Pressure overload

ASJC Scopus subject areas

  • Physiology

Cite this

Sari, F. R., Widyantoro, B., Thandavarayan, R. A., Harima, M., Lakshmanan, A., Zhang, S., Muslin, A. J., Suzuki, K., Kodama, M., & Watanabe, K. (2011). Attenuation of CHOP-mediated myocardial apoptosis in pressure-overloaded dominant negative p38α mitogen-activated protein kinase mice. Cellular Physiology and Biochemistry, 27(5), 487-496. https://doi.org/10.1159/000329970