on December 23, 2004
Published online before print December 23, 2004, doi: 10.1161/01.ATV.0000154279.98244.eb
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 23, 2004
Accepted on December 14, 2004
Human Urotensin II Is a Novel Activator of NADPH Oxidase in Human Pulmonary Artery Smooth Muscle Cells
Talija Djordjevic ;
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.
* To whom correspondence should be addressed. 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), 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 oxidase.
This article has been cited by other articles:
 |
|
 |
|
  N. Bousette, P. D'Orleans-Juste, R. S. Kiss, Z. You, J. Genest, W. Al-Ramli, S. T. Qureshi, A. Gramolini, D. Behm, E. H. Ohlstein, et al. Urotensin II Receptor Knockout Mice on an ApoE Knockout Background Fed a High-Fat Diet Exhibit an Enhanced Hyperlipidemic and Atherosclerotic Phenotype Circ. Res., September 25, 2009; 105(7): 686 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Advani, R. E. Gilbert, K. Thai, R. M. Gow, R. G. Langham, A. J. Cox, K. A. Connelly, Y. Zhang, A. M. Herzenberg, P. K. Christensen, et al. Expression, Localization, and Function of the Thioredoxin System in Diabetic Nephropathy J. Am. Soc. Nephrol., April 1, 2009; 20(4): 730 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ismail, A. Sturrock, P. Wu, B. Cahill, K. Norman, T. Huecksteadt, K. Sanders, T. Kennedy, and J. Hoidal NOX4 mediates hypoxia-induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor-{beta}1 and insulin-like growth factor binding protein-3 Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L489 - L499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 A. Cave, D. Grieve, S. Johar, M. Zhang, and A. M Shah NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology Phil Trans R Soc B, December 29, 2005; 360(1464): 2327 - 2334. [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]
|
|