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Vascular Receptor Autoantibodies in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis.
MedLine Citation:
PMID:  25181620     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Objective: Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin-1 (ET-1) and angiotensin II (Ang II) via endothelin receptor type A (ETAR) and angiotensin receptor type-1 (AT1R) activation are implicated in PAH pathogenesis. We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT1R and ETAR may contribute to SSc-PAH pathogenesis and tested their functional and biomarker relevance. Methods and Results: Anti-AT1R and -ETAR Abs detected by ELISA were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease (CTD)-associated PAH (n=110) compared to other forms of PAH/pulmonary hypertension (n=106). High anti-AT1R and anti-ETAR Abs predicted development of SSc-PAH and SSc-PAH-related mortality in a prospective analysis. Both Abs increased endothelial cytosolic Ca2+ concentrations in isolated perfused rat lungs which could be blocked by respective specific receptor antagonists. Ab-mediated stimulation of third to fourth-generation intralobar pulmonary rat artery ring segments in a myograph increased vasoconstrictive responses to Ang II and ET-1 and implicated cross-talk between both pathways demonstrated by reciprocal blockade with respective antagonists. Transfer of SSc-IgG containing both autoantibodies into healthy C57Bl/6J mice led to more abundant vascular and airway alpha-smooth muscle actin expression and inflammatory pulmonary vasculopathy. Conclusions: Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/CTD-PAH compared to other forms of PH and serve as predictive and prognostic biomarkers in SSc-PAH. Both antibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.
Authors:
Mike O Becker; Angela Kill; Marissa Kutsche; Jeannine Guenther; Angelika Rose; Christoph Tabeling; Martin Witzenrath; Anja A Kühl; Harald Heidecke; Hossein A Ghofrani; Henning Tiede; Ralph T Schermuly; Nils Nickel; Marius M Hoeper; Ivo Lukitsch; Maik Gollasch; Wolfgang M Kuebler; Sebastian Bock; Gerd R Burmester; Duska Dragun; Gabriela Riemekasten
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-9-2
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  -     ISSN:  1535-4970     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-9-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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