Published online before print November 29, 2004, doi: 10.1161/01.RES.0000151983.01148.06
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 15, 2004
Revised on November 2, 2004
Accepted on November 18, 2004
Atrial Natriuretic Peptide Induces Mitogen-Activated Protein Kinase Phosphatase-1 in Human Endothelial Cells via Rac1 and NAD(P)H Oxidase-2 Activation
Robert Fürst ;
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.
* To whom correspondence should be addressed. 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
This article has been cited by other articles:
 |
|
 |
|
  R. Furst, S. Zahler, and A. M. Vollmar Dexamethasone-Induced Expression of Endothelial Mitogen-Activated Protein Kinase Phosphatase-1 Involves Activation of the Transcription Factors Activator Protein-1 and 3',5'-Cyclic Adenosine 5'-Monophosphate Response Element-Binding Protein and the Generation of Reactive Oxygen Species Endocrinology, July 1, 2008; 149(7): 3635 - 3642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Furst, M. F. Bubik, P. Bihari, B. A. Mayer, A. G. Khandoga, F. Hoffmann, M. Rehberg, F. Krombach, S. Zahler, and A. M. Vollmar Atrial Natriuretic Peptide Protects against Histamine-Induced Endothelial Barrier Dysfunction in Vivo Mol. Pharmacol., July 1, 2008; 74(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Wu, Z. Ma, D. P. Myers, and L. S. Terada HIV-1 Tat Activates Dual Nox Pathways Leading to Independent Activation of ERK and JNK MAP Kinases J. Biol. Chem., December 28, 2007; 282(52): 37412 - 37419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-X. Zhang, X.-M. Lu, S. Kimura, and A. Nishiyama Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation Cardiovasc Res, November 1, 2007; 76(2): 204 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Li, L. Yang, J. Shen, C. Wang, and Z. Jiang The Antiproliferative Effect of Sildenafil on Pulmonary Artery Smooth Muscle Cells Is Mediated via Upregulation of Mitogen-Activated Protein Kinase Phosphatase-1 and Degradation of Extracellular Signal-Regulated Kinase 1/2 Phosphorylation Anesth. Analg., October 1, 2007; 105(4): 1034 - 1041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Furst, T. Schroeder, H. M. Eilken, M. F. Bubik, A. K. Kiemer, S. Zahler, and A. M. Vollmar MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium FASEB J, January 1, 2007; 21(1): 74 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ushio-Fukai Redox signaling in angiogenesis: Role of NADPH oxidase Cardiovasc Res, July 15, 2006; 71(2): 226 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Furst, S. B. Blumenthal, A. K. Kiemer, S. Zahler, and A. M. Vollmar Nuclear Factor-{kappa}B-Independent Anti-Inflammatory Action of Salicylate in Human Endothelial Cells: Induction of Heme Oxygenase-1 by the c-Jun N-Terminal Kinase/Activator Protein-1 Pathway J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 389 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Brueckl, S. Kaestle, A. Kerem, H. Habazettl, F. Krombach, H. Kuppe, and W. M. Kuebler Hyperoxia-Induced Reactive Oxygen Species Formation in Pulmonary Capillary Endothelial Cells In Situ Am. J. Respir. Cell Mol. Biol., April 1, 2006; 34(4): 453 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Cai Hydrogen peroxide regulation of endothelial function: Origins, mechanisms, and consequences Cardiovasc Res, October 1, 2005; 68(1): 26 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Cai NAD(P)H Oxidase-Dependent Self-Propagation of Hydrogen Peroxide and Vascular Disease Circ. Res., April 29, 2005; 96(8): 818 - 822. [Abstract] [Full Text] [PDF]
|
|