help button home button
AJRCMB
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on November 21, 2008, doi:10.1165/rcmb.2008-0153OC
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
2008-0153OCv1
40/6/683    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Google Scholar
Right arrow Articles by Laumanns, I. P.
Right arrow Articles by Voswinckel, R.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laumanns, I. P.
Right arrow Articles by Voswinckel, R.
American Journal of Respiratory Cell and Molecular Biology. Vol. 40, pp. 683-691, 2009
© 2009 American Thoracic Society
DOI: 10.1165/rcmb.2008-0153OC

The Noncanonical WNT Pathway Is Operative in Idiopathic Pulmonary Arterial Hypertension

Isabel P. Laumanns1,3, Ludger Fink2, Jochen Wilhelm2, Jens-C. Wolff1,3, Rita Mitnacht-Kraus1, Sabine Graef-Hoechst1, Maria M. Stein2, Rainer M. Bohle5, Walter Klepetko4, Mir A. R. Hoda4, Ralph T. Schermuly1,3, Friedrich Grimminger1, Werner Seeger1,3 and Robert Voswinckel1,3

1 Department of Internal Medicine, and 2 Institute of Pathology, University Hospital of Giessen, Giessen, Germany; 3 Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany; 4 Department of Cardiothoracic Surgery, University of Vienna, Vienna, Austria; and 5 Department of Pathology, University of the Saarland, Homburg/Saar, Germany

Correspondence and requests for reprints should be addressed to Robert Voswinckel, M.D., University Hospital Giessen and Marburg GmbH, Department of Internal Medicine, Klinikstrasse 36, D-35392 Giessen, Germany. E-mail: robert.voswinckel{at}innere.med.uni-giessen.de

Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease that comprises sustained vasoconstriction, enhanced proliferation of pulmonary vascular cells, and in situ thrombosis. The discovery of several contributing signaling pathways in recent years has resulted in an expanding array of novel therapies; however, IPAH remains a progressive disease with poor outcome in most instances. To identify new regulatory pathways of vascular remodeling in IPAH, we performed transcriptome-wide expression profiling of laser-microdissected pulmonary arterial resistance vessels derived from explanted IPAH and nontransplanted donor lung tissues. Statistical analysis of the data derived from six individuals in each group showed significant regulation of several mediators of the canonical and noncanonical WNT pathway. As to the noncanonical WNT pathway, the planar cell polarity (PCP) pathway, the ras homolog gene family member A (RHOA), and ras-related C3 botulinum toxin substrate-1 (RAC1) were strongly up-regulated. Real-time PCR of laser-microdissected pulmonary arteries confirmed these array results and showed in addition significant up-regulation of further PCP mediators wingless member 11 (WNT11), disheveled associated activator of morphogenesis-1 (DAAM1), disheveled (DSV), and RHO-kinase (ROCK). Immunohistochemical staining and semiquantitative expression analysis confirmed the markedly enhanced expression of the PCP mediators in the pulmonary resistance vessels, in particular in the endothelial layer in IPAH. Therefore we propose the PCP pathway to be critically involved in the regulation of vascular remodeling in IPAH.

Key Words: planar cell polarity • molecular medicine • vascular remodeling • pulmonary resistance arteries • laser-microdissection


CLINICAL RELEVANCE

This is the first compartment-specific analysis of idiopathic pulmonary arterial hypertension (IPAH) arteries. Interesting new candidates were revealed. The WNT signaling pathway was identified in the pathogenesis of IPAH and might be a potential new therapeutic approach.

 



This article has been cited by other articles:


Home page
 Am. J. Respir. Cell Mol. Bio.Home page
K. B. Adler and S. Matalon
Highlights of the November Issue
Am. J. Respir. Cell Mol. Biol., November 1, 2009; 41(5): 505 - 506.
[Full Text] [PDF]

Home page
 Cold Spring Harb. Perspect. Biol.Home page
E. K. Vladar, D. Antic, and J. D. Axelrod
Planar Cell Polarity Signaling: The Developing Cell's Compass
Cold Spring Harb Perspect Biol, September 1, 2009; 1(3): a002964 - a002964.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
C. Guilluy, S. Eddahibi, C. Agard, C. Guignabert, M. Izikki, L. Tu, L. Savale, M. Humbert, E. Fadel, S. Adnot, et al.
RhoA and Rho Kinase Activation in Human Pulmonary Hypertension: Role of 5-HT Signaling
Am. J. Respir. Crit. Care Med., June 15, 2009; 179(12): 1151 - 1158.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2009 American Thoracic Society. 		  Work-Life