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NF-κB inhibitor improves pulmonary vascular remodeling by reversing LPS-induced down-regulation of BMPRII

ZHOU Mei-Jun^1,*, XING Yan-Jiang², YANG Jun^3,2

¹State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS), School of Basic Medicine, Peking Union Medical College (PUMC), Beijing 100005, China；²State Key Laboratory of Medical Molecular Biology, Department of Cell Biology, Institute of Basic Medical Sciences, CAMS, School of Basic Medicine, PUMC, Beijing 100005, China；³Department of Physiology, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China

Abstract

The occurrence and development of pulmonary arterial hypertension (PAH) is closely related to the genetic mutation ofbone morphogenetic protein receptor type II (BMPRII) encoding gene and the inflammatory response mediated by nuclear factor κB(NF-κB) pathway. This paper was aimed to investigate the effect of NF-κB pathway inhibitors on lipopolysaccharide (LPS)-inducedpulmonary artery endothelial cell injury. Human pulmonary artery endothelial cells were treated with 1 μg/mL of LPS. The expressionlevels of BMPRII and interleukin-8 (IL-8) were detected by Western blot and qPCR. The rat PAH model was established by intraperitoneal(i.p.) injection of monocrotaline (MCT). The expression levels of BMPRII and IL-8 in pulmonary artery endothelial cells weredetected by immunofluorescence staining. Cardiac hemodynamic changes and pulmonary vascular remodeling were detected in theMCT-PAH model rats. The results showed that LPS caused down-regulation of BMPRII expression and up-regulation of IL-8 expressionin human pulmonary artery endothelial cells. NF-κB inhibitor BAY11-7082 (10 μmol/L) reversed the effect of LPS. In the pulmonaryartery endothelial cells of MCT-PAH model, BMPRII expression was down-regulated, IL-8 expression was up-regulated, weight ratioof right ventricle to left ventricle plus septum [RV/(LV+S)] and right ventricular systolic pressure (RVSP) were significantlyincreased, cardiac output (CO) and tricuspid annular plane systolic excursion (TAPSE) were significantly reduced, and pulmonaryvessel wall was significantly thickened. BAY11-7082 (5 mg/kg, i.p., 21 consecutive days) reversed the above changes in the MCT-PAHmodel rats. These results suggest that LPS down-regulates the expression level of BMPRII through NF-κB signaling pathway, promotingthe occurrence and development of PAH. Therefore, the NF-κB pathway can be used as a potential therapeutic target for PAH.

Key words: pulmonary arterial hypertension; bone morphogenetic protein receptor type II; nuclear factor κB signaling pathway; BAY11-7082

Received: 2019-10-26　　Accepted: 2020-06-02

Corresponding author: 周美君　　E-mail: yang_jun@zju.edu.cn

DOI: 10.13294/j.aps.2020.0040

Citing This Article：

ZHOU Mei-Jun, XING Yan-Jiang, YANG Jun. NF-κB inhibitor improves pulmonary vascular remodeling by reversing LPS-induced down-regulation of BMPRII. Acta Physiol Sin 2020; 72 (5): 541-550 (in Chinese with English abstract).