Plasminogen activator Inhibitor-2 inhibits pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension via PI3K/Akt and ERK signaling
Section snippets
Background
Pulmonary arterial hypertension (PAH) shares characteristics similar with malignant diseases, such as the overproliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) [1,2]. Pulmonary vascular remodeling, characterized by medial hypertrophy, intimal proliferative changes, adventitial thickening, complex lesions and thrombotic lesions, is the major pathological change of PAH [3]. The enhanced proliferation and reduced apoptosis of the PASMCs in the medial layer
Cell culture
hPASMCs isolated from healthy human pulmonary arteries were from ScienCell Research Laboratories (Carlsbad, CA, USA), and characterized by immune-fluorescent method with antibodies to α-smooth muscle actin and desmin. hPASMCs were cultured in smooth muscle cell medium (ScienCell Research Laboratories, Carlsbad, CA, USA) supplemented with 2% fetal bovine serum and 1% smooth muscle cell growth supplement, enriched at 37 °C in a 5% CO2 atmosphere. Passages three to six were used for transfection.
Overexpression and knock-down of PAI-2 in hPASMCs
Serum PAI-2 is decreased in PAH patients
We first examined serum PAI-2 level in patients with PAH. Fifty PAH patients and fifty healthy controls were enrolled in this study. Thirteen patients were diagnosed with idiopathic PAH (IPAH), 24 with connective tissue disease-associated PAH (CTD-PAH), 8 with congenital heart disease-associated PAH (CHD-PAH), 1 with portal hypertension-PAH and 4 with pulmonary veno-occlusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH). The median age of PAH patients was 36 years old and 74% of
Discussion
In this study, we observed that the serum PAI-2 was decreased in PAH patients compared with healthy controls, and PAI-2 level was negatively correlated with mPAP and eSPAP in ultrasonic cardiogram while positively correlated with 6MWD in PAH patients. In rats, administration of exogenous PAI-2 significantly reversed monocrotaline-induced PAH, as indicated by the decrease of RVSP, RVHI and %MT of pulmonary arterioles. Mechanistically, PAI-2 inhibited hPASMCs proliferation by preventing the
Conflict of interest form
No conflicts of interest, financial or otherwise, are declared by the authors.
CRediT authorship contribution statement
Shuai Zhang: Conceptualization, Methodology, Software, Formal analysis, Investigation, Data curation, Writing - original draft, Project administration, Funding acquisition. Jing Wang: Software, Validation, Investigation, Resources, Data curation. Xianmei Qi: Methodology, Investigation, Resources. Xincao Tao: Investigation, Resources. Wanmu Xie: Resources, Writing - review & editing. Jun Wan: Investigation, Resources, Writing - review & editing. Ying H. Shen: Writing - review & editing,
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 81600036 and 81570049), CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2018-I2M-1-003) and the Fund of the National Key Research and Development Program of China (No. 2016YFC0905600).
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