1. LOX-1 mediated phenotypic switching of pulmonary arterial smooth muscle cells contributes to hypoxic pulmonary hypertension.
- Author
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Zhang W, Zhu T, Wu W, Ge X, Xiong X, Zhang Z, and Hu C
- Subjects
- Animals, Cell Dedifferentiation, Cell Hypoxia, Cell Proliferation, Ether-A-Go-Go Potassium Channels metabolism, Hypertension, Pulmonary physiopathology, Male, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Myocytes, Smooth Muscle drug effects, Pulmonary Artery physiopathology, Rats, Rats, Wistar, Signal Transduction, Transcription Factors metabolism, Up-Regulation, Hypertension, Pulmonary metabolism, Hypertension, Pulmonary pathology, Myocytes, Smooth Muscle pathology, Phenotype, Pulmonary Artery pathology, Scavenger Receptors, Class E metabolism
- Abstract
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., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2018
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