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

Basic Res Cardiol. 2002 Jan;97(1):1-8. doi: 10.1007/s395-002-8381-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cells, Cultured
  • Dual Specificity Phosphatase 6
  • Endothelium / cytology
  • Endothelium / drug effects*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein Tyrosine Phosphatases / genetics*
  • Protein Tyrosine Phosphatases / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transfection
  • Up-Regulation / drug effects*


  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Angiotensin II
  • Mitogen-Activated Protein Kinases
  • DUSP6 protein, human
  • Dual Specificity Phosphatase 6
  • Protein Tyrosine Phosphatases