Journal article

Publication year: 2019

Pages: 1407-1420

Journal: American Journal of Respiratory and Critical Care Medicine

Volume number: 199

Issue number: 11

ISSN: 1073-449X

eISSN: 1535-4970

DOI Link: https://doi.org/10.1164/rccm.201806-1170OC

Publisher: American Thoracic Society

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-1 alpha (hypoxia-inducible factor 1 alpha) 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.

Harvard Citation style: Novoyatleva, T., Kojonazarov, B., Owczarek, A., Veeroju, S., Rai, N., Henneke, I., et al. (2019) Evidence for the Fucoidan/P-Selectin Axis as a Therapeutic Target in Hypoxia-induced Pulmonary Hypertension, American Journal of Respiratory and Critical Care Medicine, 199(11), pp. 1407-1420. https://doi.org/10.1164/rccm.201806-1170OC

APA Citation style: Novoyatleva, T., Kojonazarov, B., Owczarek, A., Veeroju, S., Rai, N., Henneke, I., Boehm, M., Grimminger, F., Ghofrani, H., Seeger, W., Weissmann, N., & Schermuly, R. (2019). Evidence for the Fucoidan/P-Selectin Axis as a Therapeutic Target in Hypoxia-induced Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine. 199(11), 1407-1420. https://doi.org/10.1164/rccm.201806-1170OC