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Article Dans Une Revue Circulation Année : 2023

Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension

Christopher Rhodes
Luke Howard
Martin Wilkins

Résumé

Background: Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers. Methods: Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues. Results: Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50–81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000–1.001]; P =0.037 and 1.263 [95% CI, 1.049–1.520]; P =0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001–1.005]; P =0.001 and 1.365 [95% CI, 1.185–1.573]; P <0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03–0.61; P =0.009) and 0.17 (95% CI, 0.06–0.45; P <0.001), and for follow-up measures, 0.23 (95% CI, 0.07–0.78; P =0.019) and 0.27 (95% CI, 0.09–0.78, P =0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin. Conclusions: These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.

Dates et versions

hal-04519677 , version 1 (25-03-2024)

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Christophe Guignabert, Laurent Savale, Athénaïs Boucly, Raphaël Thuillet, Ly Tu, et al.. Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension. Circulation, 2023, 147 (24), pp.1809-1822. ⟨10.1161/CIRCULATIONAHA.122.061501⟩. ⟨hal-04519677⟩
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