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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., Kill, A., Kutsche, M., Guenther, J., Rose, A., Tabeling, C., Witzenrath, M., Kühl, A.A., Heidecke, H., Ghofrani, H.A., Tiede, H., Schermuly, R.T., Nickel, N., Hoeper, M.M., Lukitsch, I., Gollasch, M., Kuebler, W.M., Bock, S., Burmester, G.R., 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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