Details

Autor(en) / Beteiligte

• Alba, George A
• Samokhin, Andriy O
• Wang, Rui-Sheng
• Zhang, Ying-Yi
• Wertheim, Bradley M
• Arons, Elena
• Greenfield, Edward A
• Lundberg Slingsby, Martina H
• Ceglowski, Julia R
• Haley, Kathleen J
• Bowman, Frederick P
• Yu, Yen-Rei
• Haney, John C
• Eng, George
• Mitchell, Richard N
• Sheets, Anthony
• Vargas, Sara O
• Seo, Sachiko
• Channick, Richard N
• Leary, Peter J
• Rajagopal, Sudarshan
• Loscalzo, Joseph
• Battinelli, Elisabeth M
• Maron, Bradley A

Titel

NEDD9 Is a Novel and Modifiable Mediator of Platelet-Endothelial Adhesion in the Pulmonary Circulation

Ist Teil von

• American journal of respiratory and critical care medicine, 2021-06, Vol.203 (12), p.1533-1545

Ort / Verlag

United States: American Thoracic Society

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. To identify a hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling. Network medicine was used to profile protein-protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography-mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet-endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models . The protein NEDD9 was identified in the hypoxia thrombosome network . Compared with normoxia, hypoxia (0.2% O ) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)-dependent NEDD9 upregulation . Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9-P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors and from patients with CTEPH . Compared with control mice, platelet-pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9 mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling . The NEDD9-P-selectin protein-protein interaction is a modifiable target with which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.