Evidence for the Fucoidan/P-Selectin Axis as a Therapeutic Target in Hypoxia-induced Pulmonary Hypertension.
Am J Respir Crit Care Med
; 199(11): 1407-1420, 2019 06 01.
Article
em En
| MEDLINE
| ID: mdl-30557519
ABSTRACT
Rationale Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Fucoidan, a polysaccharidic ligand of the adhesion molecule P-selectin, exhibits antiproliferative properties. The effects of the fucoidan/P-selectin axis on vascular remodeling and pulmonary hypertension (PH) after hypoxia remain unexplored. Objectives:
We aimed to evaluate the therapeutic potential of targeting the fucoidan/P-selectin axis in PH.Methods:
Mice with PH induced by chronic hypoxia (35 d) were given either fucoidan (from Fucus vesiculosus) or anti-P-selectin antibody (Rb40.34) during Days 21-35. Right ventricular (RV) function was determined by echocardiography. Vascular morphometry was assessed by immunohistochemistry. Human and experimental PH lungs and PASMCs were used for assessment of P-selectin expression and function. Measurements and MainResults:
Fucoidan attenuated chronic hypoxia-induced PH in mice, reducing pulmonary vascular remodeling and restoring RV function. In vitro, fucoidan inhibited hypoxia and growth factor-stimulated PASMC proliferation and migration. Chronic hypoxia caused an upregulation of P-selectin in the medial layer of the small pulmonary arteries. P-selectin was persistently upregulated in PASMCs of human and hypoxia-induced experimental PH. HIF-1α (hypoxia-inducible factor 1α) directly bound to the P-selectin promoter and transcriptionally activated P-selectin in hypoxia. P-selectin blockage resulted in a marked reduction of PASMC proliferation in vitro. Blockage of P-selectin by administration of anti-P-selectin Rb40.34 antibody and P-selectin-deficient mice improved vascular remodeling and restored RV function.Conclusions:
Fucoidan is a potent natural adjuvant that represents a promising therapeutic approach for PH. Our data indicate a previously unrecognized role of P-selectin in the proliferative response of PASMCs associated with PH.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Polissacarídeos
/
Selectina-P
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Miócitos de Músculo Liso
/
Hipertensão Pulmonar
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Hipóxia
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Anticoagulantes
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article