The role and mechanism of thrombospondin-4 in pulmonary arterial hypertension associated with congenital heart disease

作者：Haowei Zeng, Beidi Lan, Bingyi Li, Hang Xie, Enfa Zhao, Xiaoqin Liu, Xiaoyi Xue, Jingyan Sun, Linjie Su, Yushun Zhang · 发表于：Respiratory Research · 年份：2024 · DOI：10.1186/s12931-024-02932-w · 被引用次数：14 · 研究领域：Pulmonary Hypertension Research and Treatments、Angiogenesis and VEGF in Cancer、Platelet Disorders and Treatments

BACKGROUND: Due to a special hemodynamic feature, pulmonary vascular disease in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) has two stages: reversible and irreversible. So far, the mechanism involved in the transition from reversible to irreversible stage is elusive. Moreover, no recognized and reliable assessments to distinguish these two stages are available. Furthermore, we found that compared with control and reversible PAH, thrombospondin-4 (THBS4) was significantly upregulated in irreversible group by bioinformatic analysis. Hence, we further verify and investigate the expression and role of THBS4 in PAH-CHD. METHODS: We established the monocrotaline plus aorto-cava shunt-induced (MCT-AV) rat model. We measured the expression of THBS4 in lung tissues from MCT-AV rats. Double immunofluorescence staining of lung tissue for THBS4 and α-SMA (biomarker of smooth muscle cells) or vWF (biomarker of endothelial cells) to identify the location of THBS4 in the pulmonary artery. Primary pulmonary artery smooth muscle cells (PASMCs) were cultivated, identified, and used in this study. THBS4 was inhibited and overexpressed by siRNA and plasmid, respectively, to explore the effect of THBS4 on phenotype transformation, proliferation, apoptosis, and migration of PASMCs. The effect of THBS4 on pulmonary vascular remodeling was evaluated in vivo by adeno-associated virus which suppressed THBS4 expression. Circulating level of THBS4 in patients with ...