LOX-1 mediated phenotypic switching of pulmonary arterial smooth muscle cells contributes to hypoxic pulmonary hypertension

作者：Zhang, Weifang; Zhu, Tiantian; Wu, Weihua; Ge, Xiaoyue; Xiong, Xiaoming; Zhang, Zheng^*; Hu, Changping^*

来源：European Journal of Pharmacology, 2018, 818: 84-95.

DOI：10.1016/j.ejphar.2017.10.037

• LOX-1
• Pulmonary hypertension
• Pulmonary vascular remodeling
• Pulmonary arterial smooth muscle cells
• Phenotype switching
• Dedifferentiation

In pulmonary hypertension (PH), pulmonary arterial smooth muscle cells (PASMCs) are dedifferentiated, undergoing a contractile-to-synthetic phenotypic switching. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays diverse roles in the cardiovascular system, but its contribution to PH remains to be fully defined. The present study was undertaken to explore the role of LOX-1 in PASMCs dedifferentiation in hypoxia-induced pulmonary vascular remodeling and PH. In a rat model of hypoxic PH, pulmonary vascular remodeling was accompanied by increased expression of LOX-1 in pulmonary arteries. In primary rat PASMCs, hypoxia-induced PASMCs dedifferentiation occurred concomitantly with LOX-1 upregulation. Inhibition of LOX-1 by either siRNA knockdown or neutralizing antibody significantly ameliorated PASMCs dedifferentiation. Mechanistically, LOX-1 promotes PASMCs dedifferentiation under hypoxic conditions via ERK1/2-Elk-1/MRTF-A/SRF signaling pathway. In conclusion, our data uncovers an important role of LOX-1 in the maintenance of PASMCs phenotype. Therapeutic targeting of LOX-1/ERK1/2-Elk-1/MRTF-A/SRF signaling axis would be exploited to treat hypoxic PH.

• 出版日期2018-1-5
• 单位湖南大学; 中南大学; 南昌大学