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Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis

Item Type:Article
Title:Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis
Creators Name:Becker, M.O. and Kill, A. and Kutsche, M. and Guenther, J. and Rose, A. and Tabeling, C. and Witzenrath, M. and Kühl, A.A. and Heidecke, H. and Ghofrani, H.A. and Tiede, H. and Schermuly, R.T. and Nickel, N. and Hoeper, M.M. and Lukitsch, I. and Gollasch, M. and Kuebler, W.M. and Bock, S. and Burmester, G.R. and Dragun, D. and Riemekasten, G.
Abstract: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.
Keywords:Systemic Sclerosis, PAH, AT1R, ETAR, Autoantibodies, Animals, Mice, Rats
Source:American Journal of Respiratory and Critical Care Medicine
Publisher:American Thoracic Society
Page Range:808-817
Date:1 October 2014
Official Publication:https://doi.org/10.1164/rccm.201403-0442OC
PubMed:View item in PubMed

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