Circulation Research. 2002;90:874-881
Published online before print April 4, 2002, doi: 10.1161/01.RES.0000017068.58856.F3
Published online before print April 4, 2002, doi: 10.1161/01.RES.0000017068.58856.F3
© 2002 American Heart Association, Inc.
Molecular Medicine |
Inhibition of p38 MAPK Activation via Induction of MKP-1
Atrial Natriuretic Peptide Reduces TNF-
–Induced Actin Polymerization and Endothelial Permeability
From the Department of Pharmacy, Center of Drug Research, University of Munich, Munich, Germany.
Correspondence to Alexandra K. Kiemer, PhD, Dept of Pharmacy, Center of Drug Research, Butenandtstr. 5-13, 81377 Munich, Germany. E-mail Alexandra.Kiemer@ cup.uni-muenchen.de
The atrial natriuretic peptide (ANP) is a cardiovascular hormone possessing antiinflammatory potential due to its inhibitory action on the production of inflammatory mediators, such as tumor necrosis factor-
(TNF-). The aim of this study was to determine whether ANP is able to attenuate inflammatory effects of TNF- on target cells. Human umbilical vein endothelial cells (HUVECs) were treated with TNF- in the presence or absence of ANP. Changes in permeability, cytoskeletal alterations, phosphorylation of p38 MAPK and HSP27, and expression of MKP-1 were determined by macromolecule permeability assay, fluorescence labeling, RT-PCR, and immunoblotting. Antisense studies were done by transfecting cells with MKP-1 antisense oligonucleotides. Activation of HUVECs with TNF- lead to a significant increase of macromolecule permeability and formation of stress fibers. Treatment of cells with ANP (10-8 to 10-6 mol/L) significantly reduced the formation of stress fibers and elevated permeability. Both TNF-–induced effects were shown to be mediated via the activation of p38 using SB203580, a specific inhibitor of p38. ANP significantly reduced the TNF-–induced activation of p38 and attenuated the phosphorylation of HSP27, a central target downstream of p38. ANP showed no effect on p38 upstream kinases MKK3/6. However, a significant induction of the MAPK phosphatase MKP-1 mRNA and protein could be observed in ANP-treated cells. Antisense experiments proved a causal role for MKP-1 induction in the ANP-mediated inhibition of p38. These data show the inhibitory action of ANP on TNF-–induced changes in endothelial cytoskeleton and macromolecule permeability involving an MKP-1–induced inactivation of p38 MAPK. These effects point to an antiinflammatory and antiatherogenic potential of this cardiovascular hormone.
Key Words: signal transduction • inflammation • endothelium • hormones • natriuretic peptides
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