Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis

Am J Respir Crit Care Med. 2014 Oct 1;190(7):808-17. doi: 10.1164/rccm.201403-0442OC.


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 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.

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.

Keywords: angiotensin receptor type-1; autoantibodies; endothelin receptor type A; pulmonary arterial hypertension; systemic sclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Autoantibodies / blood
  • Autoantibodies / immunology*
  • Biomarkers / blood
  • Enzyme-Linked Immunosorbent Assay / methods
  • Female
  • Humans
  • Hypertension, Pulmonary / blood
  • Hypertension, Pulmonary / complications
  • Hypertension, Pulmonary / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Myography / methods
  • Prospective Studies
  • Pulmonary Artery / immunology*
  • Pulmonary Artery / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Scleroderma, Systemic / blood
  • Scleroderma, Systemic / complications
  • Scleroderma, Systemic / immunology*


  • Autoantibodies
  • Biomarkers