Liver Kinase B1 Protects Against Hypoxia-Induced Pulmonary Arterial Endothelial Cell Dysfunction via the AMP-Activated Protein Kinase Pathway.

Abstract

Pulmonary hypertension (PH) is a progressive disease characterized by vascular reHypoxiaing, endothelial cell dysfunction, and inflammation. Liver Kinase B1 (LKB1, also known as STK11) is a central regulator of cell polarity and energy homeostasis. However, its specific role and mechanism of action in PH remain unclear. Human pulmonary arterial endothelial cells (hPAECs) were cultured in vitro to establish PH cell Hypoxias under normoxic and hypoxic conditions. The expression of LKB1 was detected by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and western blotting, and its effect on hPAECs function was investigated by overexpression and inhibition of LKB1. Furthermore, cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis was measured by flow cytometry, inflammatory cytokine secretion was evaluated using enzyme-linked immunosorbent assay (ELISA), and the expression of AMP-activated protein kinase (AMPK) signaling pathway-related proteins was analyzed by western blotting. LKB1 expression was significantly reduced in hypoxia-treated hPAECs compared with that in normoxic controls, and LKB1 overexpression significantly ameliorated the hypoxia-induced decrease in cell proliferation and increase in apoptosis as well as inflammatory factor secretion. The AMPK agonist (GSK621) reversed the dysfunction caused by LKB1 inhibition, indicating that LKB1 regulates hPAECs function through the AMPK signaling pathway. LKB1 plays a protective role in PH by inhibiting hPAECs dysfunction via activation of the AMPK pathway.