This Article Full Text Full Text (PDF) All Versions of this Article: 25/3/519    most recent 01.ATV.0000154279.98244.ebv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Djordjevic, T. Articles by Görlach, A. Search for Related Content PubMed PubMed Citation Articles by Djordjevic, T. Articles by Görlach, A. Related Collections Remodeling Cell signalling/signal transduction Physiological and pathological control of gene expression Pulmonary biology and circulation Fibrinolysis Smooth muscle proliferation and differentiation Oxidant stress

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:519.)
© 2005 American Heart Association, Inc.

Vascular Biology

Human Urotensin II Is a Novel Activator of NADPH Oxidase in Human Pulmonary Artery Smooth Muscle Cells

Talija Djordjevic; Rachida S. BelAiba; Steve Bonello; Josef Pfeilschifter; John Hess; Agnes Görlach

From Experimental Pediatric Cardiology (T.D., R.S.B.A., S.B., J.H., A.G.), Clinic for Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University of Munich, Germany, and Pharmazentrum Frankfurt (J.P.), University of Frankfurt, Frankfurt, Germany.

Correspondence to Agnes Görlach, MD, Experimental Pediatric Cardiology, Clinic for Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at TU Munich, Lazarettstr 36, D-80636 Munich, Germany. E-mail goerlach{at}dhm.mhn.de

Background— Human urotensin II (hU-II) is a potent vasoactive peptide possibly involved in pulmonary hypertension. Because the signaling mechanisms activated by this peptide in the pulmonary vasculature are largely unknown, we investigated the role of hU-II in the activation of NADPH oxidase and the control of redox-sensitive kinase pathways, expression of plasminogen activator inhibitor-1 (PAI-1), and proliferation in pulmonary artery smooth muscle cells (PASMCs).

Methods and Results— hU-II upregulated expression of the NADPH oxidase subunits p22phox and NOX4 and increased the levels of reactive oxygen species (ROS), which were abrogated by transfecting p22phox or NOX4 antisense vectors. p22phox and NOX4 also contributed to hU-II–induced activation of extracellular signal–regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and protein kinase B (Akt). Furthermore, hU-II increased the expression of PAI-1 and enhanced PASMC proliferation in an NADPH oxidase– and kinase-dependent manner.

Conclusions— hU-II is a potent activator of ROS generation by NADPH oxidase in PASMCs, leading to redox-sensitive activation of mitogen-activated protein kinases and Akt and subsequently to enhanced PAI-1 expression and increased proliferation. These findings suggest that hU-II may play a novel role in pulmonary hypertension by promoting remodeling processes via activation of NADPH oxidases.

Human urotensin-II (hU-II) is a potent vasoactive peptide with largely unknown effects on pulmonary artery smooth muscle cells. hU-II activated NADPH oxidase and elevated the levels of p22phox and NOX4, leading to enhanced phosphorylation of MAP kinases and protein kinase B and subsequently increased PAI-1 expression and cell proliferation.

Key Words: reactive oxygen species • p22phox • NOX4 • urotensin II • plasminogen activator inhibitor-1

This article has been cited by other articles:

				K. Chen, M. T. Kirber, H. Xiao, Y. Yang, and J. F. Keaney Jr. Regulation of ROS signal transduction by NADPH oxidase 4 localization J. Cell Biol., October 22, 2008; 181(7): 1129 - 1139. [Abstract] [Full Text] [PDF]

				Md. R. Abid, K. C. Spokes, S.-C. Shih, and W. C. Aird NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways J. Biol. Chem., November 30, 2007; 282(48): 35373 - 35385. [Abstract] [Full Text] [PDF]

				S. Bonello, C. Zahringer, R. S. BelAiba, T. Djordjevic, J. Hess, C. Michiels, T. Kietzmann, and A. Gorlach Reactive Oxygen Species Activate the HIF-1{alpha} Promoter Via a Functional NF{kappa}B Site Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 755 - 761. [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]

				C. E. Murdoch, M. Zhang, A. C. Cave, and A. M. Shah NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure Cardiovasc Res, July 15, 2006; 71(2): 208 - 215. [Abstract] [Full Text] [PDF]

				T. Watanabe, T. Suguro, T. Kanome, Y.-i. Sakamoto, S. Kodate, T. Hagiwara, S. Hongo, T. Hirano, M. Adachi, and A. Miyazaki Human Urotensin II Accelerates Foam Cell Formation in Human Monocyte-Derived Macrophages Hypertension, October 1, 2005; 46(4): 738 - 744. [Abstract] [Full Text] [PDF]