Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis

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

*Corresponding author for this work
112 Citations (Scopus)


Rationale: Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin (ET) 1 and angiotensin (Ang) II via endothelin receptor type A (ETAR) and Ang receptor type-1 (AT1R) activation are implicated in PAH pathogenesis. Objectives: 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: Anti-AT1R and -ETAR Abs were detected by ELISA in different cohorts of patients and tested in vitro and in an animal model for their pathophysiological effects. Measurements and Main Results: The Abs were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n = 110) compared with 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 intralobar pulmonary rat artery ring segments 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 α-smooth muscle actin expression and inflammatory pulmonary vasculopathy. Conclusions: Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/connective tissue disease-PAH compared with other forms of pulmonary hypertension, 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.

Original languageEnglish
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number7
Pages (from-to)808-817
Number of pages10
Publication statusPublished - 01.10.2014

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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