Evidence for the Fucoidan/P-Selectin Axis as a Therapeutic Target in Hypoxia-induced Pulmonary Hypertension

• Published in: American journal of respiratory and critical care medicine 2019-06, Vol.199 (11), p.1407-1420
• Main Authors: Novoyatleva, Tatyana, Kojonazarov, Baktybek, Owczarek, Andreas, Veeroju, Swathi, Rai, Nabham, Henneke, Ingrid, Böhm, Mario, Grimminger, Friedrich, Ghofrani, Hossein A, Seeger, Werner, Weissmann, Norbert, Schermuly, Ralph T
• Format: Article
• Language: English
• Subjects: Algae; Animals; Anticoagulants - therapeutic use; Apolipoproteins; Atherosclerosis; Biomarkers - blood; Blood platelets; Cell adhesion & migration; Disease Models, Animal; Experiments; Fucus - chemistry; Growth factors; Humans; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - physiopathology; Hypoxia; Hypoxia - complications; Hypoxia - physiopathology; Inflammation; Male; Mice; Myocytes, Smooth Muscle - drug effects; P-Selectin - blood; Polysaccharides - therapeutic use; Pulmonary arteries; Pulmonary hypertension; Smooth muscle; Statistical analysis
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201806-1170OC

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. We aimed to evaluate the therapeutic potential of targeting the fucoidan/P-selectin axis in PH. Mice with PH induced by chronic hypoxia (35 d) were given either fucoidan (from ) 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. Fucoidan attenuated chronic hypoxia-induced PH in mice, reducing pulmonary vascular remodeling and restoring RV function. , 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 . 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. 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.