Published online before print November 29, 2004, doi: 10.1161/01.RES.0000151983.01148.06
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© 2005 American Heart Association, Inc.
Molecular Medicine |
Atrial Natriuretic Peptide Induces Mitogen-Activated Protein Kinase Phosphatase-1 in Human Endothelial Cells via Rac1 and NAD(P)H Oxidase/Nox2-Activation
From the Department of Pharmacy (R.F., S.Z., A.M.V., A.K.K.), the Institute for Surgical Research (C.B.), and Institute of Physiology (F.K.), University of Munich, Germany; Institute of Physiology (W.M.K.), Campus Benjamin Franklin, Charité, Berlin, Germany; Experimental Pediatric Cardiology (A.G.), German Heart Center Munich, Technical University Munich, Germany; and The Scripps Research Institute (A.K.K.), La Jolla, Calif.
Correspondence to Alexandra K. Kiemer, PhD, The Scripps Research Institute, Molecular and Experimental Medicine, Mail MEM 131, 10550 N Torrey Pines Rd, La Jolla, CA 92037. E-mail kiemer{at}scripps.edu
The cardiovascular hormone atrial natriuretic peptide (ANP) exerts anti-inflammatory effects on tumor necrosis factor-
–activated endothelial cells by inducing mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1). The underlying mechanisms are as yet unknown. We aimed to elucidate the signaling pathways leading to an induction of MKP-1 by ANP in primary human endothelial cells. By using antioxidants, generation of reactive oxygen species (ROS) was shown to be crucially involved in MKP-1 upregulation. ANP was found to increase ROS formation in cultured cells as well as in the endothelium of intact rat lung vessels. We applied NAD(P)H oxidase (Nox) inhibitors (apocynin and gp91ds-tat) and revealed this enzyme complex to be crucial for superoxide generation and MKP-1 expression. Moreover, by performing Nox2/4 antisense experiments, we identified Nox2 as the critically involved Nox homologue. Pull-down assays and confocal microscopy showed that ANP activates the small Rho-GTPase Rac1. Transfection of a dominant-negative (RacN17) and constitutively active Rac1 mutant (RacV12) indicated that ANP-induced superoxide generation and MKP-1 expression are mediated via Rac1 activation. ANP-evoked production of superoxide was found to activate c-Jun N-terminal kinase (JNK). Using specific inhibitors, we linked ANP-induced JNK activation to MKP-1 expression and excluded an involvement of protein kinase C, extracellular signal-regulated kinase, and p38 MAPK. MKP-1 induction was shown to depend on activation of the transcription factor activator protein-1 (AP-1) by using electrophoretic mobility shift assay and AP-1 decoys. In summary, our work provides insights into the mechanisms by which ANP induces MKP-1 and shows that ANP is a novel endogenous activator of endothelial Rac1 and Nox/Nox2.
Key Words: endothelium • natriuretic peptides • signal transduction • Rac1 • Nox2
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