Skip Navigation


Cardiovascular Research Advance Access first published online on September 17, 2009
This version [Corrected Proof] published online on October 8, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp313
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
cvp313v2    most recent
cvp313v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
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 Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Post, S.
Right arrow Articles by Goumans, M.-J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Post, S.
Right arrow Articles by Goumans, M.-J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Impaired recruitment of HHT-1 mononuclear cells to the ischaemic heart is due to an altered CXCR4/CD26 balance

Simone Post1,2,{dagger}, Anke M. Smits1,{dagger}, Alexandra J. van den Broek1, Joost P.G. Sluijter1, Imo E. Hoefer1, Ben J. Janssen3, Repke J. Snijder4, Johannes J. Mager4, Gerard Pasterkamp1,2, Christine L. Mummery2,5, Pieter A. Doevendans1,2 and Marie-José Goumans1,*

1 Department of Cardiology, Division Heart & Lung, UMCU, Utrecht, the Netherlands
2 Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands
3 Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, the Netherlands
4 Department of Pulmonary Disease, St Antonius Hospital, Nieuwegein, the Netherlands
5 Department of Anatomy and Embryology, LUMC, Leiden, the Netherlands

* Corresponding author: Department of Molecular Cell Biology, LUMC, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands. Tel: +31 71 526 9277, Fax: +31 71 526 8270, Email: m.j.goumans{at}lumc.nl

Aims: Mononuclear cells (MNCs) from patients with hereditary haemorrhagic telangiectasia type 1 (HHT1), a genetic disorder caused by mutations in endoglin, show a reduced ability to home to infarcted mouse myocardium. Stromal cell-derived factor-1{alpha} (SDF-1{alpha}) and the chemokine receptor CXCR4 are crucial for homing and negatively influenced by CD26. The aim of this study was to gain insight into the impaired homing of HHT1-MNCs.

Methods and results: CXCR4 and CD26 expression on MNCs was determined by flow cytometry. Transwell migration to SDF-1{alpha} was used to analyse in vitro migration. Experimentally induced myocardial infarction in mice, followed by tail vein injection of MNCs, was applied to study homing in vivo. HHT1-MNCs expressed elevated levels of CXCR4, but this was counterbalanced by high levels of CD26, resulting in decreased migration towards an SDF-1{alpha} gradient in vitro. Migration was enhanced by inhibiting CD26 with Diprotin-A. While MNCs from healthy controls responded to transforming growth factor-beta stimulation by increasing CXCR4 and lowering CD26 expression levels, HHT1-MNCs did not react as efficiently: in particular, CD26 expression remained high. Inhibiting CD26 on MNCs increased the homing of human cells into the infarcted mouse heart. Interestingly, the defect in homing of HHT1-MNCs was restored by pre-incubating the HHT1-MNCs with Diprotin-A before injection into the tail vein.

Conclusion: We show that a decreased homing of HHT1-MNCs is caused by an impaired ability of the cells to respond to SDF-1{alpha}. Our results suggest that modulating CD26 levels using inhibitors like Diprotin-A can restore homing in cases where increased expression of CD26 contributes to the underlying pathological mechanism.

KEYWORDS Mononuclear cells; Chemokines; Genetics; Myocardial infarction; Migration

Time for primary review: 35 days

{dagger} These authors contributed equally to the work.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.