Journalartikel

Jahr der Veröffentlichung: 2014

Seiten: 808-817

Zeitschrift: American Journal of Respiratory and Critical Care Medicine

Bandnummer: 190

Heftnummer: 7

ISSN: 1073-449X

eISSN: 1535-4970

DOI Link: https://doi.org/10.1164/rccm.201403-0442OC

Verlag: American Thoracic Society

Abstract: 

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 (AT(1)R) activation are implicated in PAH pathogenesis.

Objectives: We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT(1)R and ETAR may contribute to SSc-PAH pathogenesis, and tested their functional and biomarker relevance.

Methods: Anti-AT(1)R 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-AT(1)R 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/6) mice led to more abundant vascular and airway alpha-smooth muscle actin expression and inflammatory pulmonary vasculopathy.

Conclusions: Anti-AT(1)R 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.

Harvard-Zitierstil: Becker, M., Kill, A., Kutsche, M., Guenther, J., Rose, A., Tabeling, C., et al. (2014) Vascular Receptor Autoantibodies in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis, American Journal of Respiratory and Critical Care Medicine, 190(7), pp. 808-817. https://doi.org/10.1164/rccm.201403-0442OC

APA-Zitierstil: Becker, M., Kill, A., Kutsche, M., Guenther, J., Rose, A., Tabeling, C., Witzenrath, M., Kuehl, A., Heidecke, H., Ghofrani, H., Tiede, H., Schermuly, R., Nickel, N., Hoeper, M., Lukitsch, I., Gollasch, M., Kuebler, W., Bock, S., Burmester, G., ...Riemekasten, G. (2014). Vascular Receptor Autoantibodies in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis. American Journal of Respiratory and Critical Care Medicine. 190(7), 808-817. https://doi.org/10.1164/rccm.201403-0442OC