Journal Article

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

Seeger, Werner, Henneke, Ingrid, Novoyatleva, Tatyana, Rai, Nabham, Schermuly, Ralph T., Ghofrani, Hossein A., Kojonazarov, Baktybek, Böhm, Mario, Weissmann, Norbert, Veeroju, Swathi, Owczarek, Andreas, Grimminger, Friedrich

2019

Overview

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 Main Results 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.

• Publisher: Oxford University Press
• Subject: 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