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Basic Research in Cardiology

, Volume 97, Issue 1, pp 1–8 | Cite as

Angiotensin II-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apotosis

  • Lothar Rössig
  • Corinna Hermann
  • Judith Haendeler
  • Birgit Assmus
  • Andreas M. Zeiher
  • Stefanie Dimmeler
ORIGINAL CONTRIBUTION

Abstract

Angiotensin II (Ang II) is central to the pathobiology of atherosclerosis. In endothelial cells (EC), Ang II induces apoptosis. The MAP kinase ERK1/2 plays a key role in regulating cell survival. We therefore investigated the effect of Ang II on ERK1/2. Incubation of EC with Ang II led to the dephosphorylation of ERK1/2 (43 % of control). To characterize the phosphatase involved, we investigated the effect of Ang II on MAP kinase phosphatase expression. Ang II induced MAP kinase phosphatase-3 (MKP-3) mRNA levels to about 2-fold, whereas MKP-1 expression was not affected. Transfection with a dominant negative MKP-3 construct (dnMKP-3mt) prevented the Ang II-induced ERK1/2 dephosphorylation and apoptosis in EC (p < 0.001). ERK1/2 inactivation has been shown to result in the dephosphorylation and proteasomal degradation of the antiapoptotic protein Bcl-2. Ang II induced the degradation of Bcl-2 wild type, whereas the dephosphorylation-resistant Bcl-2 construct mimicking phosphorylation by ERK1/2 was resistant to Ang II stimulation. These results indicate that Ang II-induced apoptosis signaling in human EC is mediated via MKP-3-dependent dephosphorylation of ERK1/2, which in turn leads to the degradation of Bcl-2.

Key words Angiotensin II – apoptosis – endothelial cell – signal transduction – kinases 

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Copyright information

© Steinkopff Verlag 2002

Authors and Affiliations

  • Lothar Rössig
    • 1
  • Corinna Hermann
    • 1
  • Judith Haendeler
    • 1
  • Birgit Assmus
    • 1
  • Andreas M. Zeiher
    • 1
  • Stefanie Dimmeler
    • 1
  1. 1.Molecular Cardiology, Department of Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany, Tel.: +49-69/6301-7440, Fax: +49-69/6301-7113, E-Mail: dimmeler@em.uni-frankfurt.deDE

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