CD248 as a novel therapeutic target in pulmonary arterial hypertension. Issue 5 (17th September 2020)

• Record Type: Journal Article
• Authors: Xu, Tao; Shao, Lei; Wang, Aimei; Liang, Rui; Lin, Yuhan; Wang, Guan; Zhao, Yan; Hu, Jing; Liu, Shuangyue
• Is Part Of: Clinical and translational medicine. Volume 10:Issue 5(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-09-17
• Subjects: CD248 -- NOX4 -- oxidative stress -- PDGF‐BB -- pulmonary arterial hypertension; Clinical medicine -- Periodicals; Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 616.027
• DOI: 10.1002/ctm2.175
• Languages: English
• ISSNs: 2001-1326

Abstract

Abstract: Pulmonary vascular remodeling is the most important pathological characteristic of pulmonary arterial hypertension (PAH). No effective treatment for PAH is currently available because the mechanism underlying vascular remodeling is not completely clear. CD248, also known as endosialin, is a transmembrane protein that is highly expressed in pericytes and fibroblasts. Here, we evaluated the role of CD248 in pulmonary vascular remodeling and the processes of PAH pathogenesis. Activation of CD248 in pulmonary artery smooth muscle cells (PASMCs) was found to be proportional to the severity of PAH. CD248 contributed to platelet‐derived growth factor‐BB (PDGF‐BB)‐induced PASMC proliferation and migration along with the shift to more synthetic phenotypes. In contrast, treatment with Cd248 siRNA or the anti‐CD248 therapeutic antibody (ontuxizumab) significantly inhibited the PDGF signaling pathway, obstructed NF‐κB p65‐mediated transcription of Nox4, and decreased reactive oxygen species production induced by PDGF‐BB in PAMSCs. In addition, knockdown of CD248 alleviated pulmonary vascular remodeling in rat PAH models. This study provides novel insights into the dysfunction of PASMCs leading to pulmonary vascular remodeling, and provides evidence for anti‐remodeling treatment for PAH via the immediate targeting of CD248. Abstract : CD248 as a novel therapeutic target in pulmonary arterial hypertension. Expression of CD248 contributed to platelet‐derived growth factor‐BB (PDGF‐BB)‐induced PASMC proliferation and migration along with the shift to more synthetic phenotypes. Besides, treatment of human PASMCs with PDGF‐BB, to explore the PAH signaling, exhibited ERK and NF‐κB activation, enhanced NOX4 activity, and reactive oxygen species production.