Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension.
J Clin Invest
; 128(5): 1956-1970, 2018 05 01.
Article
en En
| MEDLINE
| ID: mdl-29629897
ABSTRACT
Pulmonary arterial hypertension (PAH) is characterized by a progressive accumulation of pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterioles leading to the narrowing of the lumen, right heart failure, and death. Although most studies have supported the notion of a role for IL-6/glycoprotein 130 (gp130) signaling in PAH, it remains unclear how this signaling pathway determines the progression of the disease. Here, we identify ectopic upregulation of membrane-bound IL-6 receptor (IL6R) on PA-SMCs in PAH patients and in rodent models of pulmonary hypertension (PH) and demonstrate its key role for PA-SMC accumulation in vitro and in vivo. Using Sm22a-Cre Il6rfl/fl, which lack Il6r in SM22A-expressing cells, we found that these animals are protected against chronic hypoxia-induced PH with reduced PA-SMC accumulation, revealing the potent pro-survival potential of membrane-bound IL6R. Moreover, we determine that treatment with IL6R-specific antagonist reverses experimental PH in two rat models. This therapeutic strategy holds promise for future clinical studies in PAH.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Arteria Pulmonar
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Ratones Transgénicos
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Regulación hacia Arriba
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Miocitos del Músculo Liso
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Receptor gp130 de Citocinas
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Hipertensión Pulmonar Primaria Familiar
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Remodelación Vascular
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Músculo Liso Vascular
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Clin Invest
Año:
2018
Tipo del documento:
Article