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  • Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis.

Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis.

American journal of respiratory and critical care medicine (2014-09-03)
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
ABSTRACT

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. 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. 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. 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 Ca(2+) 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Valsartan, ≥98% (HPLC)
Valsartan for peak identification, European Pharmacopoeia (EP) Reference Standard
Valsartan, European Pharmacopoeia (EP) Reference Standard
USP
Valsartan, United States Pharmacopeia (USP) Reference Standard
Supelco
Valsartan, Pharmaceutical Secondary Standard; Certified Reference Material
Valsartan for system suitability, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Anti-GATM antibody produced in rabbit, affinity isolated antibody