Document Detail


A Critical Role for Egr-1 during Vascular Remodelling in Pulmonary Arterial Hypertension.
MedLine Citation:
PMID:  25028387     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
AIMS: Pulmonary arterial hypertension (PAH) is characterized by development of unique neointimal lesions in small pulmonary arteries, leading to increased right ventricular (RV) afterload and -failure. Novel therapeutic strategies are needed that target these neointimal lesions. Recently, the transcription factor Egr-1 was demonstrated to be upregulated early in experimental neointimal PAH. Its effect on disease development, however, is unknown. We aimed to uncover a novel role for Egr-1 as a molecular inductor for disease development in PAH.
METHODS AND RESULTS: In experimental flow-associated PAH in rats, we investigated the effects of Egr-1 downregulation on pulmonary vascular remodelling, including neointimal development, and disease progression. Intravenous administration of catalytic oligodeoxynucleotides (DNAzymes) resulted in downregulation of pulmonary vascular Egr-1 expression. Compared to vehicle or scrambled-DNAzymes, DNAzymes attenuated pulmonary vascular remodelling, including the development of occlusive neointimal lesions. Selective downregulation of Egr-1 in vivo led to reduced expression of vascular PDGF-B, TGF-β, IL-6 and p53 resulting in a reduction of vascular proliferation and increased apoptosis. DNAzyme treatment further attenuated pulmonary vascular resistance, right ventricular systolic pressure and right ventricular hypertrophy. In contrast, in non-neointimal PH rodents DNAzyme treatment had no effect on pulmonary vascular and RV remodelling. Finally, pharmacological inhibition of Egr-1 with pioglitazone, a PPAR-γ ligand, attenuated vascular remodelling including of neointimal development.
CONCLUSIONS: These results indicate that Egr-1 governs pulmonary vascular remodelling and the development of characteristic vascular neointimal lesions in flow-associated PAH. Egr-1 is therefore a potential target for future PAH treatment.
TRANSLATIONAL PERSPECTIVE: PAH is characterized by the development of unique neointimal lesions. PAH is regarded incurable when these neointimal lesions have formed. New therapeutic strategies are needed that target these neointimal lesions. Here we investigated whether Egr-1 could be such a target. We show that a) Egr-1 governs pulmonary neointimal development in experimental PAH and b) Egr-1 is a putative new treatment target for PAH patients.
Authors:
Michael G Dickinson; Piotr S Kowalski; Beatrijs Bartelds; Marinus A J Borgdorff; Diederik van der Feen; Hannie Sietsma; Grietje Molema; Jan A A M Kamps; Rolf M F Berger
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-7-14
Journal Detail:
Title:  Cardiovascular research     Volume:  -     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2014 Jul 
Date Detail:
Created Date:  2014-7-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
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