The association of neuron-derived orphan receptor 1 with pulmonary vascular remodeling in COPD patients

Abstract

Chang-Guo Wang,1,* Chang Li,2,* Wei Lei,1 Jun-Hong Jiang,1 Jian-An Huang,1 Da-Xiong Zeng1 1Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Thoracic Surgery, First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China *These authors contributed equally to this work Introduction: Chronic hypoxia-induced pulmonary vascular remodeling is a feature of chronic obstructive pulmonary disease (COPD). Our previous reports indicate that neuron-derived orphan receptor 1 (NOR1) promoted pulmonary smooth muscle cell proliferation in vitro. But it remains unclear whether NOR1 participated into hypoxia-induced pulmonary vascular remodeling in COPD patients. Patients and methods: For this study, we collected peripheral lung tissues of 26 male COPD patients with or without hypoxemia. We detected the pulmonary vascular remodeling in all the peripheral lung tissues. Primary human pulmonary arterial smooth muscle cells were also cultured in vitro and stimulated with hypoxia or normoxia. Cell proliferation and protein levels were detected.Results: COPD patients with hypoxemia showed significantly enlarged pulmonary vessels wall thickness and increased protein levels of HIF-1α, smooth muscle actin, cyclin D1, and NOR1 when compared with those in normoxic patients. Moreover, hypoxia induced human pulmonary arterial smooth muscle cell proliferation and NOR1 overexpression in vitro. The plasmid-based NOR1 gene overexpression markedly promoted DNA synthesis and proliferation in hypoxia or normoxic cells. Human NOR1 gene-specific siRNA intensively suppressed DNA synthesis and proliferation. Transfection of NOR1 overexpression plasmid raised cyclin D1 protein levels, which could be significant inhibited by NOR1-specific siRNA or a CDK4/6 inhibitor PD0332991.Conclusion: We concluded that NOR1 upregulation is associated with hypoxia-induced pulmonary vascular remodeling in COPD via promoting human pulmonary arterial smooth muscle cell proliferation. Keywords: pulmonary arterial smooth muscle cells, neuron-derived orphan receptor 1, cyclin D1, hypoxia, pulmonary vascular remodeling

Keywords

• pulmonary arterial smooth muscle cells
• neuron-derived orphan receptor 1
• cyclin D1
• hypoxia
• pulmonary vascular remodeling